PH-dependent NMDA receptor antagonists

ABSTRACT

NMDA receptor blockers, including pH-sensitive NMDA receptor blockers, are provided as neurprotective drugs that are useful in stroke, traumatic brain injury, epilepsy, and other neurologic events that involve acidification of brain or spinal cord tissue. Compositions and methods of this invention are used for treating neurodegeneration resulting from NMDA receptor activation. The compounds described herein have enhanced activity in brain tissue having lower than normal pH due to pathological conditions such as hypoxia resulting from stroke, traumatic brain injury, global ischemia that may occur during cardiac surgery, hypoxia that may occur following cessation of breathing, pre-eclampsia, spinal cord trauma, epilepsy, chrounic pain, vascular dementia and glioma rumors. Compounds described herein are also useful in preventing neurodegeneration in patients with Parkinson&#39;s Alzheimer&#39;s, Huntington&#39;s chorea, ALS, and other neurodegenerative conditions known to the art to be responsive to treatment using NMDA receptor blockers. Prefebably the compounds provided herein are allosteric NMDA inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. patent application No.60/274,205, filed Mar. 8, 2001, which is incorporated herein byreference to the extent not inconsistent herewith.

BACKGROUND

NMDA receptors are a subtype of glutamate-gated ion channels thatmediate excitatory synaptic transmission between neurons in the centralnervous system (Dingledine, R. et al., [1999], “The glutamate receptorion channels,” Pharmacological Reviews 51:7-61). NMDA receptors are asubtype of the most widespread excitatory neurotransmitter receptor inthe brain. Excessive activation of NMDA receptors kills neurons, andcurrent evidence implicates NMDA receptor activation in a variety ofneurologic disorders that include epilepsy, ischemic brain damage,traumatic brain/spinal cord injury, and Alzheimer's Diseases,Huntington's chorea and Amyotrophic Lateral Sclerosis (ALS).

In animal models of stroke and brain trauma, glutamate released fromaffected neurons can overstimulate NMDA receptors, which in turn causesneuronal death. Because overactivation of NMDA receptors is neurotoxic,compounds that block NMDA receptors have been considered candidates fortreatment of stroke or head injuries. Numerous animal studies havevalidated NMDA receptors as targets for neuroprotection in stroke, brainand spinal cord trauma, and related settings that involve brain ischemiaNMDA receptor blockers are effective in limiting the volume of damagedbrain tissue in experimental models of stroke and traumatic braininjury. (Choi, D. (1998), “Antagonizing excitotoxicity: A therapeuticstrategy for stroke,” Mount Sinai J. Med. 65:133-138; Dirnagle, U. etal. (1999) “Pathobiology of ischaemic stroke: an integrated view,” Tr.Neurosci. 22:391-397; Obrenovitch, T. P. and Urenjak, J. (1997) “Is highextracellular glutamate the key to excitotoxicity in traumatic braininjury,” J. Neurotrauma 14:677-698.) In addition, NMDA receptorantagonists are known to be anti-convulsant in many experimental modelsof epilepsy (Bradford, H. R. [1995] “Glutamate, GABA, and Epilepsy,”Progress in Neurobiology 47:477-511; McNamara, J. O. [2001] Drugseffective in the therapy of the epilepsies. In Goodman & Gliman's: Thepharmacological basis of therapeutics [Eds. J. G. Hardman and L. E.Limbird] McGraw Hill, New York). However, dose-limiting side effectshave thus far prevented clinical use of NMDA receptor antagonists forthese neurologic conditions (Muir, K. W. and Lees, K. R. [1995]“Clinical experience with excitatory amino acid antagonist drugs,”Stroke 26:503-513; Herrling, P. L., ed. [1997] “Excitatory aminoacid—clinical results with antagonists” Academic Press; Parsons, C. G.et al. [1998] “Glutamate in CNS disorders as a target for drugdevelopment: an update,” Drug News Perspective 11:523-569), andconsequently enthusiasm for this receptor protein as a drug target hasdiminished within the pharmaceutical industry. NMDA receptor blockersalso act synergistically with L-DOPA to relieve symptoms ofParkinsonism. In addition, such compounds are useful for treatingchronic neuropathic pain and bipolar disorder. However, the first threegenerations of NMDA receptor antagonists (channel blockers, competitiveblockers of the glutamate or glycine agonist sites, and noncompetitiveallosteric antagonists) have not proved useful clinically.

Several recent papers have suggested that rapidly-growing brain gliomascan kill adjacent neurons by secreting glutamate and overactivating NMDAreceptors The dying neurons make room for the growing tumor, and mayrelease cellular components that stimulate tumor growth. These studiesshown NMDA receptor antagonists can reduce the rate of tumor growth invivo as well as in some in vitro models. (Takano, T., et al. (2001),“Glutamate release promotes growth of malignant glioma,” Nature Medicine7:1010-1015; Rothstein, J. D. and Bren, H. (2001), “Excitotoxicdestruction facilitates brain tumor growth,” Nature Medicine 7:994-995;Rzeski, W., et al. (2001), “Glutamate antagonists limit tumor growth,”Proc. Nat'l Acad. Sci 98:6372-6377.)

In the late 1980's a new class of NMDA receptor antagonists(phenylethanolamines) was discovered which did not bind at the agonistbinding sites. This class, exemplified by the compound ifenprodil,selectively interacts with NMDA receptors containing the NR2B subunit.These compounds have exhibited neuroprotective properties in preclinicalmodels. This class of antagonist lacks the severe side-effect liabilityof other types of NMDA antagonists (e.g. PCP-like psychotic symptoms andcardiovascular effects).

One of the most prevalent subtypes of NMDA receptor which contains theNR2B subunit has the unusual property of being normally inhibited byprotons by about 50% at physiological pH (Traynelis, S. F. andCull-Candy, S. G. [1990] “Proton inhibition of N-methyl-D-aspartatereceptors in cerebellar neurons,” Nature 345:347-350. We have found thatphenylethanolamines, typified by ifenprodil and CP101,606 inhibitactivation of NMDA receptors by potentiating allosteric inhibitionmediated by protons. In turn, small reduction of pH in the physiologicalrange increases the potency of some phenylethanol-amines as NMDAreceptor antagonists. The potency of ifenprodil for inhibition of NR2Bsubunit-containing recombinant NMDA receptors is enhanced at pH 6.8compared to pH 7.5. (Mott et al. [1998], “Phenylethanolamines inhibitNMDA receptors by enhancing proton inhibition,” Nature Neuroscience1(8):659-667.) Ischemic brain tissue, as well as the site of seizuregeneration in epilepsy, is characterized by a lower pH than is found inbrain tissue.

Therapeutic compounds for the foregoing pathologies may have toxic sideeffects. It is thus an object of this invention to provide compoundswhich have enhanced activity under the lower pH conditionscharacteristic of such pathologies, and which are less active under thenormal pH conditions of healthy brain tissue.

A number of patents discuss NMDA receptor antagonists, including U.S.Pat. No. 6,080,743 to Acklin et al.; U.S. Pat. Nos. 4,924,008 and4,957,909 to Abou-Gharbia et al.; U.S. Pat. Nos. 5,889,026, 5,952,344,6,071,929, 6,265,426, and 6,339,093 to Alanine et al.; U.S. Pat. No.5,633,379 to Allgeier; U.S. Pat. Nos. 5,922,716, 5,753,657 and 5,777,114to Aloup et al.; U.S. Pat. No. 5,124,319 to Baudy et al.; U.S. Pat. No.5,179,085 to Bigge et al.; U.S. Pat. No. 5,962,472 to Bourson et al.;U.S. Pat. Nos. 5,919,826, 6,007,841, 6,054,451, and 6,187,338 to Carusoet al.; U.S. Pat. Nos. 5,498,610, 5,594,007, 5,710,168, and 6,258,827 toChenard et al.; U.S. Pat. Nos. 5,888,996 and 6,083,941 to Farb; U.S.Pat. No. 5,981,553 to Farr et al.; U.S. Pat. Nos. 5,866,585, 6,057,373,and 6,294,583 to Fogel; U.S. Pat. No. 6,274,633 to Franks et al.; U.S.Pat. No. 5,385,947 to Godel et al.; U.S. Pat. Nos. 6,034,134 and6,071,966 to Gold et al.; U.S. Pat. No. 5,714,500 to Griffith et al.;U.S. Pat. Nos. 5,563,157 and 5,606,063 to Harrison et al.; U.S. Pat. No.5,395,822 to Izumi et al.; U.S. Pat. No. 5,118,675 to Jirkovsky et al.;U.S. Pat. No. 6,177,434 to Kopke et al.; U.S. Pat. No. 5,132,313 toKozikowski et al.; U.S. Pat. Nos. 5,321,012, 5,502,058, 5,556,838,5,654,281, 5,834,479, 5,840,731, 5,863,922, and 5,869,498 to Mayer etal.; U.S. Pat. Nos. 5,318,985, 5,441,963 and 5,489,579 to McDonald etal.; U.S. Pat. No. 6,284,776 to Meltzer; U.S. Pat. No. 6,180,786 toMetz, Jr.; U.S. Pat. No. 5,783,572 to Mowbray et al.; U.S. Pat. No.6,200,990 to Namil et al.; U.S. Pat. No. 5,783,700 to Nichols et al.;U.S. Pat. Nos. 5,034,400, 5,039,528, 5,474,990, 5,605,911, 5,616,580,5,629,307, 5,767,130, 5,834,465, 5,902,815, 5,925,634, and 5,958,919 toOlney et al.; U.S. Pat. No. 5,990,126 to Park et al.; U.S. Pat. No.5,013,540 to Redburn; 6,025,369 to Rosenquist et al.; U.S. Pat. Nos.5,106,847, 5,189,054 5,491,153, 5,519,048 5,675,018, and 5,703,107 toSalituro et al.; U.S. Pat. No. 6,096,743 to Shishikura et al.; U.S. Pat.No. 6,242,456 to Shuster et al.; U.S. Pat. No. 6,194,00 to Smith et al.;U.S. Pat. No. 6,197,820 to Sontheimer et al.; U.S. Pat. No. 5,385,903 toSteppuhn et al.; U.S. Pat. No. 5,710,139 to Swahn; U.S. Pat. No.5,192,751 to Thor; U.S. Pat. No. 5,614,509 to Turski et al.; U.S. Pat.Nos. 4,906,779, 5,093,525, 5,190,976, 5,262,568, 5,336,689, 5,559,154,5,637,622, 5,767,162, 5,798,390, and 6,251,948 to Weber et al.; U.S.Pat. No. 5,095,009, 5,194,430, 5,326,756, 5,470,844, and 5,538,958 toWhitten; U.S. Pat. No. 6,284,774 to Wright et al.; U.S. Pat. No.5,587,384 and Re U.S. Pat. No. 36,397 to Zhang et al.; and U.S. Pat. No.4,994,467 to Zimmerman. However, NMDA receptor blockers are needed whichare enhanced at low pHs characteristic of certain pathologicalconditions for treatment of such pathological conditions.

All publications referred to herein are incorporated by reference to theextent not inconsistent herewith.

SUMMARY

This invention provides NMDA receptor blockers, including pH-sensitiveNMDA receptor blockers, as neuroprotective drugs that are useful instroke, traumatic brain injury, epilepsy, and other neurologic eventsthat involve acidification of brain or spinal cord tissue. Compositionsand methods of this invention are used for treating neurodegenerationresulting from NMDA receptor activation. The compounds described hereinhave enhanced activity in brain tissue having lower-than-normal pH dueto pathological conditions such as hypoxia resulting from stroke,traumatic brain injury, global ischemia that may occur during cardiacsurgery, hypoxia that may occur following cessation of breathing,pre-eclampsia, spinal cord trauma, epilepsy, status epilepticus,neuropathic or inflammatory pain, chronic pain, vascular dementia andglioma tumors. Because tumors produce an acidic environment, drugsactivated by low pH are useful in slowing tumor growth because they haveenhanced activity only at the site of the tumor. Compounds describedherein are also useful in preventing neurodegeneration in patients withParkinson's Alzheimer's, Huntington's chorea, ALS, and otherneurodegenerative conditions known to the art to be responsive totreatment using NMDA receptor blockers. Preferably the compoundsprovided herein are allosteric NMDA inhibitors.

Also preferably, the compounds provided herein are selective NMDAreceptor blockers, that is, they do not interact with other receptors orion channels at therapeutic concentrations. General blocking of NMDAreceptors throughout the brain causes adverse effects such as ataxia,memory deficits, hallucinations and other neurological problems.

The compounds provided herein block the NR2B-containing NMDA receptors,have varying activity against receptors containing NR2A or NR2D, and maybe selective for other members of the NMDA receptor family (NR2C, NR3Aand NR3B).

The novel small molecule NMDA receptor antagonists of this invention areuseful both in the treatment of stroke and head trauma in the emergencyroom setting, and for use as prophylactic agents for at risk patients.The acid generated by ischemic tissue during stroke is harnessed as aswitch to activate the neuroprotective agents described herein. In thisway side effects are minimized in unaffected tissue since drug at thesesites are less active. These compounds reduce the amount of neuronaldeath associated with stroke and head trauma. These compounds also havemilitary uses as a neuroprotective for battlefield head trauma. They maybe given chronically to individuals with epilepsy or who are at risk forstroke or head trauma, preoperatively in high risk heart/brain surgery,etc., in order to lengthen the window of opportunity for subsequenttherapy.

This invention provides the following useful for treating conditionscharacterized by lowered brain-tissue pH, selected from the groupconsisting of (R)- and (S)-enantiomers and mixtures thereof of compoundsof the formula:

wherein one of R₉, R₁₀, R₁₁, R₁₂ and R₁₈ is

where R₁₃ is alkyl, aralkyl or aryl; where R₁₇ is H or lower alkyl; andthe others of R₉, R₁₀, R₁₁, R₁₂ and R₁₈ are H, F, Cl, I or R wherein Ris lower alkyl; or:

wherein R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the groupconsisting of H, F, Cl, Br, I, and R wherein R is lower alkyl, and R₁₃is alkyl aralkyl or aryl;

wherein A is selected from the group consisting of:

-   -   wherein R₁ and R₅ are independently H or F; R₂, R₃ and R₄ are        independently selected from the group consisting of H, F, Cl,        Br, I and OR where R is lower alkyl, or R₂ and R₃ taken together        are O—CH₂—O;

-   -   wherein R₁, R₄, and R₅ are independently selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl, R₃        is independently O, S, NH or NR, R₂ is N, and R₁₆ is C-alkyl,        C-aralkyl or C-aryl;

-   -   wherein R₁, R_(4,) and R₅ are independently selected from the        group consisting of H, F, Cl, Br, I and OR where R is lower        alkyl, R₂ is independently O, S, NH or NR, R₃ is N; and R₁₆ is        C-alkyl, C-aralkyl or C-aryl;

-   -   wherein R₁ through R₄ are independently selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl, or        R₂ and R₃ taken together are O—CH₂—O;

-   -   wherein R₁, R₂ and R₃ are independently selected from the group        consisting of O, S, NH or NR where R is lower alkyl, or R₂ and        R₃ taken together are O—CH₂—O, and R₄ is N;

-   -   wherein R₂ and R₃ are independently selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl; and        R₄ is N;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR where R is lower alkyl; R₂ is N, and R₃ and R₄ are        independently selected from the group consisting of H, F, Cl,        Br, I and OR where R is lower alkyl;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR where R is lower alkyl; R₂ and R₄ are N, and R₃ is        independently selected from the group consisting of H, F, Cl,        Br, I and OR where R is lower alkyl;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR where R is lower alkyl; R₂ is selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl; and        R₃ and R₄ are N;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR where R is lower alkyl; and R₂, R₃ and R₄ are N;

-   -   wherein R₁ and R₃ are independently selected from the group        consisting of O, S, NH and NR where R is lower alkyl; and R₂,        R₂′ and R₄ are independently selected from the group consisting        of H, F, Cl, Br, I and OR where R is lower alkyl;

-   -   wherein R₁ and R₂ are independently selected from the group        consisting of O, S, NH and NR where R is lower alkyl; and R₂′,        and R₃ and R₄ are independently selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl;

-   -   wherein X, is C—R₃ or N, X₂ is C—R₄ or N, X₃ is C—R₄′ or N where        R₁—R₄′ are independently selected from the group consisting of        O, S, NH and NR where R is lower alkyl, or where R₁ and R₂ taken        together are O—CH₂—O;    -   and wherein B is selected from the group consisting of:

-   -   wherein R₆ and R₆′ are independently H or F; and R₇ is H, lower        n-alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr, or CH₂CHF₂Ar; and R. is OH,        OR, where R is lower alkyl, or F;

-   -   wherein R₆ and R₆′ are independently H or F; R₇ is CH₂ and R₈ is        O;

-   -   wherein R₅, R₆ and R₇ are independently CH₂, CHR or CR₂ where R        is lower alkyl; and R₈ is OH, OR, where R is lower alkyl, or F;

-   -   wherein R₆ and R₇ are independently CH₂, CHR or CR₂ where R is        lower alkyl; and R₈ is OH, OR, where R is lower alkyl, or F;

-   -   wherein R₆ and R₇ are independently CH₂, CHR or CR2 where R is        lower alkyl; R₈ is OH or F; and n=1-3; and

pharmaceutically acceptable salts, enantiomers, enantiomeric mixtures,and mixtures of the foregoing.

These compounds are preferably provided in combination with a suitablepharmaceutical carrier.

Preferred compounds of this invention include (R)- and (S)-enantiomersand mixtures thereof of compounds selected from the group consisting of:

-   -   wherein R₁ and R₅ are independently H or F; and    -   when R₁ and R₅ are H, R₂, R₃ and R₄ are independently selected        from the group consisting of H, F, Cl, Br, I and OR where R is        lower alkyl, and R₂ and R₃ taken together are O—CH₂—O; R₆ and        R₆′ are independently H or F; R₇ is selected from the group        consisting of lower n-alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr and        CH₂CF₂Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl,        4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alkyl, or F; R₉, R₁₀, R₁₁, and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br I and lower alkyl; and        R₁₃ is alkyl, aralkyl or aryl; and    -   when one of R₁ or R₅ is F and the other is H or F, R₂, R₃ and R₄        are independently selected from the group consisting of H, F,        Cl, Br, I and OR where R is lower alkyl and R₂ and R₃ taken        together are O—CH₂—O; R₆ and R₆′ are independently H or F; R₇ is        selected from the group consisting of H, lower n-alkyl, CH₂Ar,        CH₂CH₂Ar, CH₂CHFAr and CH₂CF₂Ar, where Ar is aryl,        2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,        2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br I and lower alkyl; and        R₁₃ is alkyl, aralkyl or aryl;

-   -   wherein R₁ and R₅ are independently H or F; R₂ is N; R₃ is O, S,        NH or NR where R is lower alkyl; R₄ is selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl, R₆        and R₆′ are independently H or F; R₇ is selected from the group        consisting of H, lower n-alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr and        CH₂CF₂Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl,        4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br I and lower alkyl; R₁₃        is alkyl, aralkyl or aryl; and R₁₆ is C-alkyl, C-aralkyl or        C-aryl;

wherein R₁ and R₅ are independently H or F; R₂ is independently O, S, NHor NR where R is lower alkyl; —R₃ is N; R₄ is selected from the groupconsisting of H, F, Cl, Br, I and OR wherein R is lower alkyl, R₆ andR₆′ are independently H or F; R₇ is selected from the group consistingof H, lower n-alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr and CH₂CF₂Ar, where Ar isaryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,6-difluorophenyl, 2,3,4-trifluorophenyl, or2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower alkyl, or F;R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the groupconsisting of H, F, Cl, Br I and lower alkyl; R₁₃ is alkyl, aralkyl oraryl; and R₁₆ is C-alkyl, C-aralkyl, or C-aryl;

-   -   wherein R₁ through R₅ are independently selected from the group        consisting of H, F, Cl, Br, I and OR₁₄, and R₂ and R₃ taken        together are O—CH₂—O; R₆ and R₆′ are independently H or F; R₇ is        CH₂, R₈ is O; R₉, R₁₀, R₁₁ and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br, I and lower alkyl;        R₁₃ is alkyl, aralkyl or aryl; R₁₄ is C-alkyl, C-aralkyl or        C-aryl; and R₁₅ is lower alkyl;

-   -   wherein R₁, R₄ and R₅ are independently selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R₂        is O, S, NH or NR₁₅; R₃ is N; R₆ and R₆′ are independently H or        F; R₇ is CH₂; R₈ is O; R₉, R₁₀, R₁₁ and R₁₂ are independently        selected from the group consisting of H, F, Cl, Br, I and lower        alkyl; R₁₃ is alkyl, aralkyl or aryl; R₁₅ is lower alkyl; and        R₁₆ is C-alkyl, C-aralkyl or C-aryl;

-   -   wherein R₁, R₄ and R₅ are independently selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R₂        is N; R₃ is O, S, NH or NR₁₅; R₆ and R₆′ are independently H or        F; R₇ is CH₂, R₈ is O, R₉, R₁₀, R₁₁ and R₁₂ are independently        selected from the group consisting of H, F, Cl, Br, I and lower        alkyl, R₁₃ is alkyl, aralkyl or aryl; R₁₅ is lower alkyl; and        R₁₆ is C-alkyl, C-aralkyl or C-aryl;

-   -   wherein R₁ and R₄ are independently selected from the group        consisting of H, F, Cl, Br, I and OR₁₄; R₂ and R₃ are        independently selected from the group consisting of F, Cl, Br,        I, and OR₁₄, and R₂ and R₃ taken together are O—CH₂—O; R₅, R₆        and R₇ are independently CH₂, CHR₁₅ or C(R₁₅)₂; R₈ is OH, OR,        where R is lower alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are        independently selected from the group consisting of H, F, Cl,        Br, I or lower alkyl; R₁₃ is alkyl, aralkyl or aryl; and R₁₄ is        C-alkyl, C-aralkyl or C-aryl;

-   -   wherein R₁ and R₄ are independently selected from the group        consisting of H, F, Cl, Br, I and OR₁₄; R₂is selected from the        group consisting of O, S, NH or NR₁₅; R₃ is N; R₅, R₆and R₇ are        independently CH₂, CHR₁₅ or C(R₁₅)₂; R₈ is OH, OR, where R is        lower alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently        selected from the group consisting of H, F, Cl, Br, I and lower        alkyl, R₁₃ is alkyl, aralkyl or aryl; R₁₄is C-alkyl, C-aralkyl        or C-aryl; R₁₅ is lower alkyl; and R₁₆ is C-alkyl, C-aralkyl, or        C-aryl;

-   -   wherein R₁ and R₄ are independently selected from the group        consisting of H, F, Cl, Br, I and OR₁₄; R₂ is N; R₃ is selected        from the group consisting of O, S, NH and NR₁₅; R₅, R₆ and R₇        are independently CH₂, CHR₁₅ or C(R₁₅)₂; R₈ is OH, OR, where R        is lower alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently        selected from the group consisting of H, F, Cl, Br, I and lower        alkyl, R₁₃ is alkyl, aralkyl or aryl; R₁₄ is C-alkyl, C-aralkyl        or C-aryl, R₁₅ is lower alkyl; and R₁₆ is C-alkyl, C-aralkyl, or        C-aryl;

-   -   wherein R₁, R₂, R₃, R₄ and R₅ are independently selected from        the group consisting of H, F, Cl, Br, I and OR₁₄, and where R₂        and R₃ taken together are O—CH₂—O; R₁ and R₇ are independently        CH₂, CHR₁₅ or C(R₁₅)₂, R₈ is OH, OR, where R is lower alkyl, or        F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the        group consisting of H, F, Cl, Br, I and lower alky, R₁₃ is        alkyl, aralkyl or aryl; R₁₄ is C-alkyl, C-aralkyl or C-aryl, and        R₁₅ is lower alkyl; and n=1-3;

-   -   )wherein R₁, R₄ and R₅ are independently selected form the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R₂        is O, S, NH or NR₁₅; R₃ is N; R₆ and R₇ are independently CH₂,        CHR₁₅ or C(R₁₅)₂; R₈ is OH, OR, where R is lower alkyl, or F;        R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the group        consisting of H, F, Cl, Br, I and lower alkyl, R₁₃ is alkyl,        aralkyl or aryl; R₁₅ is lower alkyl; R₁₆ is C-alkyl, C-aralkyl        or C-aryl; and n=1-3;

-   -   wherein R₁, R₄ and R₅ are independently selected form the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R₂        is N; R₃ is O, S, NH or NR_(15;) R₆ and R₇ are independently        CH₂, CHR₁₅ or C(R₁₅)₂; R₈ is OH, OR, where R is lower alkyl, or        F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the        group consisting of H, F, Cl, Br, I and lower alkyl, R₁₃ is        alkyl, aralkyl or aryl; R₁₅ is lower alkyl; R₁₆ is C-alkyl,        C-aralkyl or C-aryl; and n=1-3;

-   -   wherein R₁, R₂, R₃, R₄ and R₅ are independently selected from        the group consisting of H, F, Cl, Br, I and OR where R is lower        alkyl, and where R₂ and R₃ taken together are O—CH₂—O; R₆ and R₇        are independently CH₂, CHR₁₅ or C(R₁₅)₂, R₈ is OH, OR, where R        is lower alky, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently        selected from the group consisting of H, F, Cl, Br, I or lower        alkyl, R₁₃ is alkyl, aralkyl or aryl; R₁₅ is lower alkyl; and        n=1-3;

-   -   wherein R₁, R₄ and R₅ are independently selected form the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R₂        is O, S, NH or NR₁₅; R₃is N; R₆ and R₇ are independently CH₂,        CHR₁₅ or C(R₁₅)₂; R₈ is OH, OR, where R is lower alkyl, or F;        R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the group        consisting of H, F, Cl, Br, I and lower alkyl, R₁₃ is alkyl,        aralkyl or aryl; R₁₅ is lower alkyl; R₁₆ is C-alkyl, C-aralkyl        or C-aryl; R₁₆ is C-alkyl, C-aralkyl or C-aryl; and n=1-3;

-   -   wherein R₁, R₄ and R₅ are independently selected form the group        consisting of H, F, Cl, Br, I and or where R is lower alkyl; R₂        is N; R₃is O, S, NH or NR₁₅; R₆ and R₇ are independently CH₂,        CHR₁₅ or C(R₁₅)₂; R₈ is OH, OR, where R is lower alkyl, or F;        R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the group        consisting of H, F, Cl, Br, I and lower alkyl, R₁₃is alkyl,        aralkyl or aryl; R₁₅ is lower alkyl; R₁₆ is C-alkyl, C-aralkyl        or C-aryl, and n=1-3;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR₁₅; R₂, R₃ and R₄ are independently selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R₅        is H; R₆ and R₆′ are independently H or F; R₇ is H, lower alkyl,        CH₂Ar, CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl,        2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,        2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alky, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from        the group consisting of H, F, Cl, Br, I and lower alkyl; R₁₃ is        alkyl, aralkyl or aryl; and R₁₅ is lower alkyl;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR₁₅; R₂ and R₃ are independently selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl, and        R₂ and R₃ taken together are O—CH₂—O; R₄, R₅ and R₆ are        independently CH₂, CHR₁₅ or C(R₁₅)₂; R₇ is H, R₈ is OH, OR,        where R is lower alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are        independently selected from the group consisting of H, F, Cl,        Br, I and lower alky; R₁₃ is alkyl, aralkyl or aryl; and R₁₅ is        lower alkyl;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR₁₅; R₂ and R₃ are independently selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl, and        R₂ and R₃ taken together are O—CH₂—O; R₄ is N; R₅ is H; R₆ and        R₆′ are independently H or F; R₇ is H, lower alkyl, CH₂Ar,        CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl,        2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,        2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br, I and lower alkyl;        R₁₃ is alkyl, aralkyl or aryl; and R₁₅ is lower alkyl;

-   -   wherein R₁ and R₂ are independently selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R₃        is selected from the group consisting of O, S, NH and NR₁₅; R₄        is N; R₅ is H; R₆ and R₆′ are independently H or F; R₇ is H,        lower alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is        aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,        2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br, I and lower alkyl;        R₁₃ is alkyl, aralkyl or aryl; and R₁₅ is lower alkyl;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR15; R₂ is N; R₃ and R₄ are is selected from the group        consisting of H, F, Cl, Br, I and OR where R is lower alkyl; R₅        is H, R₆ and R₆′ are independently H or F; R₇ is H, lower alkyl,        CH₂Ar, CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl,        2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,        2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br, I and lower alkyl;        R₁₃ is alkyl, aralkyl or aryl; and R₁₅ is lower alkyl;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR₁₅; R₂ is N; R₃ is selected from the group consisting of H, F,        Cl, Br, I and OR where R is lower alkyl; R₄, R₅ and R₆ are        independently CH₂, CHR₁₅ or C(R₁₅)₂; R₇ is H; R₈ is OH, OR,        where R is lower alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are        independently selected from the group consisting of H, F, Cl,        Br, I or lower alkyl; R₁₃ is alkyl, aralkyl or aryl; and R₁₅ is        lower alkyl;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR₁₅; R₃ is selected from the group consisting of H, F, Cl, Br,        I and OR where R is lower alkyl; R₂ and R₄ are N; R₅ is H; R₆        and R₆′ are independently H or F; R₇ is H, lower alkyl, CH₂Ar,        CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl,        2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,        2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br, I and lower alkyl;        R₁₃ is alkyl, aralkyl or aryl; and R₁₅ is lower alkyl;

-   -   wherein R₁ is selected from the group consisting of O, S, NH and        NR₁₅; R₂ is selected from the group consisting of H, F, Cl, Br,        I and Or where R is lower alkyl; R₃ and R₄ are N; R₅ is H; R₆        and R₆′ are independently H or F; R₇ is H, lower alkyl, CH₂Ar,        CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl,        2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,        2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br, I and lower alkyl;        R₁₃ is alkyl, aralkyl or aryl; and R₁₅ is lower alkyl;

-   -   wherein R₁ is selected from a group consisting of O, S, NH or        NR₁₅; R₂, R₃ and R₄ are N; R₅ is H, R₆ and R₆′ are independently        H or F; R₇ is selected from the group consisting of H, lower        alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl,        2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,        2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br, I and lower alkyl;        R₁₃ is alkyl, aralkyl or aryl; and R₁₅ is lower alkyl;

-   -   wherein R₁ and R₃ are independently selected from the group        consisting of O, S, NH and NR₁₅; R₂, R₂′ and R₄ are        independently selected from the group consisting of H, F, Cl,        Br, I and OR where R is lower alkyl; R₅ is H; R₆ and R₆′ are        independently H or F; R₇ is H, lower alkyl, CH₂Ar, CH₂CH₂Ar,        CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl, 2-fluorophenyl,        3-fluorophenyl, 4-fluorophenyl, 2,6difluorophenyl,        2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R₈ is OH,        OR, where R is lower alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are        independently selected from the group consisting of H, F, Cl,        Br, I or lower alkyl; R₁₃ is alkyl, aralkyl or aryl; and R₁₅ is        lower alkyl;

-   -   wherein R₁ and R₂ are independently selected from the group        consisting of O, S, NH and NR₁₅; R₂′, R₃ and R₄ are        independently selected from the group consisting of H, F, Cl,        Br, I and OR where R is lower alkyl; R is H; R₆ and R₆′ are        independently H or F; R₇ is H, lower alkyl, CH₂Ar, CH₂CH₂Ar,        CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl, 2-fluorophenyl,        3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl,        2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R₈ is OH,        OR, where R is lower alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are        independently selected from the group consisting of H, F, Cl,        Br, I and lower alkyl; R₁₃ is alkyl, aralkyl or aryl; and R₁₅ is        lower alkyl;

-   -   wherein R₁ and R₄ are independently selected from the group        consisting of O, S, NH and NR₁₅; R₂ and R₃ are independently        selected from the group consisting of H, F, Cl, Br, I and OR        where R₁₄, and R₂ and R₃ taken together are O—CH₂—O; R₅, R₆ and        R₇ are independently CH₂, CHR₁₅ or C(R₁₅)₂; R₈ is OH, OR, where        R is lower alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently        selected from the group consisting of H, F, Cl, Br, I and lower        alkyl; R₁₃ is alkyl, aralkyl or aryl; R₁₄ is C-alkyl, C-aralkyl        or C-aryl and R₁₅ is lower alkyl;

-   -   wherein R₁ and R₂ are independently selected from the group        consisting of O, S, NH and NR₁₅; R₂′, R₃ and R₄ are        independently selected from the group consisting of H, F, Cl,        Br, I and OR₁₄, and R₃ and R₄ taken together are O—CH₂—O; R₅, R₆        and R₇ are independently CH₂, CHR₁₅ or C(R₁₅)₂; R₈ is OH, OR,        where R is lower alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are        independently selected from the group consisting of H, F, Cl,        Br, I and lower alkyl; R₁₃ is alkyl, aralkyl or aryl; R₁₄ is        C-alkyl, C-aralkyl or C-aryl, and R₁₅ is lower alkyl;

-   -   wherein R₁, R₂, R₃ and R₄ are independently selected from the        group consisting of H, F, Cl, Br, I and OR where R is lower        alkyl; and where R₁ and R₂ taken together are O-CH₂—O; R₅ is H,        R₆ and R₆′ are independently H or F; R₇ is H or lower alkyl,        CH₂Ar, CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl,        2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,        2,6-difluorophenyl, 2,3,4-trifluorophenyl, or        2,3,4,5,6-pentafluorophenyl; R₈ is OH, OR, where R is lower        alkyl, or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected        from the group consisting of H, F, Cl, Br, I and lower alkyl;        R₁₃ is alkyl, aralkyl or aryl; R₁₅ is lower alkyl; and X₁ is        C—R₃ or N; X2 is C—R₄ or N; and X₃ is C—R₄′ or N;

-   -   wherein R₁, R₂, R₃ and R₄ are independently selected from the        group consisting of H, F, Cl, Br, I and OR₁₄, and where R₁ and        R₂ taken together are O—CH₂—O; R₅, R₆ and R₇ are independently        CH₂, CHR₁₅ or C(R₁₅)₂; R₈ is OH, OR, where R is lower alkyl, or        F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the        group consisting of H, F, Cl, Br, I or lower alkyl; R₁₃ is        alkyl, aralkyl or aryl; R₁₄ is C-alkyl, C-aralkyl or C-aryl; R₁₅        is lower alkyl; and X₁ is C—R₂ or N; X₂ is C—R₃ or N; and X₃ is        C—R₄ or N.

Derivatives of the above compounds in which 5-membered rings contain O,S or N heteroatoms and 6-membered rings contain N heteroatoms are alsoprovided herein. (R)- and (S)-forms, and racemic mixtures thereof, ofthe foregoing compounds are also provided herein.

Other preferred compounds are those selected from the group consistingof the (S) or (R) forms and racernic mixtures of:

-   -   1-(4-methanesulphonamidepheoxy)3-(N-methyl-3,4-dichlorophenylethylamino)-2-propanol;    -   1-(4-Methanesulphonamidephenoxy)-3-(3,4-dichlorophenylethyl-amino)-2-propanol;    -   1-(4-Methanesulphonamidephenoxy)-3-(N-ethyl-3,4-dichloro-phenylethylamino)-2-propanol;    -   1-(4-Methanesulphonamidephenoxy)3-(N-propyl-3,4-dichloro-phenylethylamino)-2-propanol;    -   1-(4-Methanesulphonamidephenoxy)-3-(N-butyl-3,4-dichloro-phenylethylamino)-2-propanol;    -   1-(4-Methanesulphonamidephenoxy)-3-(N-benzyl-3,4-dichloro-phenylethylamino)-2-propanol;    -   1-(4-Methanesulphonamidephenoxy)-3-(N-(2-fluorobenzyl)-3,4-dichlorophenylethyl-amino)-2-propanol;    -   1-(4-Methanesulphonamidephenoxy)-3-(N-(3-fluorobenzyl)-3,4-dichlorophenylethyl-amino)-2-propanol;    -   1-4-Methanesulphonamidephenoxy)-3-(N-(3-fluorobenzyl)-3,4-dichloro-phenylethylamino)-2-propanol;    -   1-4-Methanesulphonamidephenoxy)-3-(N-(2,6-difluorobenzyl)-3,4-dichloro-phenylethylamino)-2-propanol;    -   1-(4-Methanesulphonamidephenoxy)-3-(N-(2,3,4-trifluorobenzyl)-3,4-dichlorophenylethylamino)-2-propanol;    -   1-(4-Methanesulphonamidephenoxy)-3-(N-(2,3,4,5,6-pentafluoro-benzyl)-3,4-dichlorophenylethylamino)-2-propanol;    -   1-(4-Methanesulphonamidephenoxy)-3-(N-(2-hydroxyethyl)-3,4-dichlorophenylethylamino)-2-propanol;    -   1-(3-Methanesulphonamidephenoxy)3-(3,4-dichlorophenylethyl-amino)-2-propanol;    -   1-(2-Methanesulphonamidephenoxy)-3-(3,4-dichlorophenyl-ethylamino)-2-propanol;    -   1-(4-Methanesulphonamidophenoxy)-3-(N-acetyl-3,4-dichloro-phenylethylamino)-2-propylacetate;    -   N-(3,4-dichlorophenyl)ethyl-5-(4-methanesulphonamidophenoxy)methyl-oxazolidine-2-one;    -   1-(4-N-methyl-methanesulphonamidephenoxy)-3-(3,4-dichloro-phenylethylamino)-2-propanol;    -   1-4-benzenesulphonamidophenoxy)-3-(3,4-dichloro-phenylethyl-amino)-2-propanol;    -   1-(4-Nitrophenoxy)3-(3,4-dichlorophenylethylamino)-2-propanol;    -   mixtures thereof and pharmaceutically acceptable salts thereof.

This invention also provides a method of treating neurodegenerationassociated with a pathological condition characterized by loweredbrain-tissue pH, said method comprising administering to a patient inneed of such treatment a pharmaceutically effective amount of a compoundhaving enhanced NMDA receptor blocking activity at said loweredbrain-tissue pH over normal brain-tissue pH, said compound beingselected from the group consisting of the above-described compounds.

The methods of this invention also include treating neurodegenerationassociated with a pathological condition characterized by loweredbrain-tissue pH, said method comprising administering to a patient inneed of such treatment a pharmaceutically effective amount of a compoundhaving enhanced NMDA receptor blocking activity at said loweredbrain-tissue pH over normal brain-tissue pH, said compound beingselected from the group consisting of: zolantidine dimaleate;2-(4-chloroanilino)-4-(4-phenylpiperazino)cyclopent-2-en-1-one;haloperidol; cirazoline; 1,10-phenanthroline;6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptanecarboxamide;(R,S)1-(4-methanesulfonamidophenoxy)-3-(N-methyl-3,4-dichlorophenylethylamine)-2-propanolhydrochloride (AM92016, compound 93);3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine;8-[2-(1,4-benzodiaxan-2-ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9-dione;(±)-8-hydroxy-2-dipropylaminotetralin hydrobromide;(±)-7-hydroxy-2-dipropylaminotetralin hydrobromide;8-[3-(4-fluorophenoxy)propyl]-1-phenyl-1,3,8-triazospiro[4.5]-decan-4-one(AMI 193); PPHT; 4-(4-fluorobenzoyl)-1-(4-phenylbutyl)piperidine;2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI); benextramine;trifluoperidol; clobenpropit; and benoxathian.

This invention also provides a method of treating neurodegenerationassociated with a pathological condition characterized by loweredbrain-tissue pH, said method comprising administering to a patient inneed of such treatment a pharmaceutically effective amount of a compoundhaving enhanced NMDA receptor blocking activity at said loweredbrain-tissue pH over normal brain-tissue pH, said compound beingselected from the group consisting of (R)- or (S)-enantiomers ormixtures thereof of compounds of the formula:

-   -   wherein one of R₉, R₁₀, R₁₁ and R₁₂ and R₁₈ is

where R₁₃ is alkyl, aralkyl or aryl; where R₁₇ is H or lower alkyl; andthe others of R₉, R₁₀, R₁₁, R₁₂ and R₁₈ are H, F, Cl, I or R wherein Ris lower alkyl; or:

-   -   wherein R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the        group consisting of H, F, Cl, Br, I, and R wherein R is lower        alkyl, and R₁₃ is alkyl aralkyl or aryl;

wherein A is a bulky, ring-containing group;

and wherein B is selected from the group consisting of:

-   -   wherein R₆ and R₆′ are independently H or F; and R₇ is H, lower        n-alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr, or CH₂CHF₂Ar; and R₈ is OH,        OR, where R is lower alkyl, or F;

-   -   wherein R₆ and R₆′ are independently H or F; R₇ is CH₂ and R₈ is        O;

-   -   wherein R₅, R₆ and R₇ are independently CH₂, CHR or _(CR) ₂        where R is lower alkyl; and R₈ is OH, OR, where R is lower        alkyl, or F;

-   -   wherein R₆ and R₇ are independently CH₂, CHR or CR₂ where R is        lower alkyl; and R₈ is OH, OR, where R is lower alkyl, or F;

-   -   wherein R₆ and R₇ are independently CH₂, CHR or CR₂ where R is        lower alkyl; R₈ is OH, OR, where R is lower alkyl, or F; and        n=1-3; and

pharmaceutically acceptable salts, enantiomers, enantiomeric mixtures,and mixtures of the foregoing.

The novel compounds disclosed herein may be used to treat pathologicalconditions not involving lowered brain-tissue pH, as well aspathological conditions involved lowered pH. Such conditions includeParkison's Disease, Alzheimers, and Amyotrophic Lateral Sclerosis (ALS).

This invention also provides methods of making compounds describedherein comprising:

-   the (S)- or (R)-form of a compound having the formula:

-   wherein R₁ is CH₃ or H, R₂ is H, and R₃ is selected from the group    consisting of NHSO₂CH₃, N(CH₃)SO₂CH₃, NHSO₂Ph and NO₂, said method    comprising reacting an (S) or (R)-glycidyl (R)-R₃-phenyl ether with    N-methyl-3,4-dichlorophenylethylamine to form the compound wherein    R₁ is CH₃; or with 3,4-dichlorophenylethylamine to form the compound    of the above formula wherein R₁ is H.

This invention also comprises a method of forming a further compound ofsaid formula wherein R₁ is selected from the group consisting of C₂H₅,C₃H₇, C₄H₉, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,2,6-difluorobenzyl, and 2,3,4-trifluorobenzyl, said method comprisingreacting the product of the foregoing method wherein R₁ is H with 1,2dichloroethane to form said further compound.

A further method is provided for forming a further compound of saidformula wherein R₁ is C₂H₄—OH, wherein said method further comprisesreacting a product of the above formula wherein R₁ is H with O-butyrylglycoaldehyde to give a second reaction product; and further reactingsaid second reaction product with sodium methoxide to form said furthercompound.

A further method is provided of forming a further compound of saidformula wherein R₁ is acetyl comprising reacting the compound of theabove formula wherein R₁ is H with N,N-dimethylaminopyridine and aceticanhydride.

A further method is provided further comprising forming a furthercompound of said formula wherein R₁ and R₂ taken together are CH₂—O—CH₂comprising reacting the compound of the above formula wherein R₁ is Hwith 1,1′-carbonyldiimidazole and N,N-dimethylaminopyridine in benzene.

R3 may be a meta- or para-substituent in the reaction intermediates andin the final product. Intermediates and corresponding final products maybe in the (S)- or (R)-forms.

A method is also provided for making (S)- or(R)-1-(2-methanesulphonamidephenoxy)-3-(3,4-dichlorophenylethylamino)-2-propanol)comprising the steps of:

-   -   (a) reacting 2-nitrophenol with (S)- or (R)-glycidyl nosylate to        form (S)- or (R)-glycidyl o-nitrophenyl ether;    -   (b) reacting the product of step (a) with        3,4-dichloropentylethylamine to form (S) or        (R)-1-(2-nitrophenyoxy)-3-(3,4-dichlorophenylethylamino)-2-propanol;    -   (c) reacting the product of step (b) with p-tolune-sulphonic        acid and benzaldehyde to form        2-phenyl-3(N-phenylethylamino)-5-(4-nitrophenoxymethyl)oxazolidine;    -   (d) reacting the product of step (c) with sodium hydroxide to        form 2-phenyl-3(N-phenylethylamino)-5-(4-aminophenoxy        methyl)oxazolidine; and    -   (e) reacting the product of step (d) with diisopropylamine and        methansulfonylchloride to form        1-2-methanesulphoneamidephenoxy)-3-(3,4-dichlorophenylethylamino)-2-propanol.

A method is also provided for making (S)- or(R)-1-(4-N-methyl-methanesulphonamidephenoxy)-3-(3,4-dichlorophenylethylamino)-2-propanolcomprising:

-   -   (a) reacting (S)- or (R)-blycidyl N-methylsulfonyl-p-aminophenyl        ether with potassium carbonate and methyl iodide to form (S)- or        (R)-glycidyl N-methyl-N-methanesulfonyl-p-aminophenyl ether;    -   (b) reacting the product of step a) with        3,4-dichlorophenylethylamine to form (S)-or        (R)-1-(4-N-methyl-methanesulphonamidephenoxy)-3-(3,4-dichlorophenylethylamino)-2-propanol.

A method is also provided for making (S)- or(R)-(1-(4-benzenesulphonamideophenoxy)-3-(3,4-dichloro-phenylethylamino)-2-propanolcomprising reacting (S)- or (R)-glycidyl N-methylsulfonyl-aminophenylether with N,N-diisopropyl-N-ethylamine to form (S)- or (R)-glycidylN-benzenesulfonyl-p-aminophenyl ether, and reacting said ether with3,4-dichlorophenylethylamine to form said (S)- or(R)-(1-(4-benzenesulphonamideophenoxy)-3-(3,4-dichloro-phenylethylamino)-2-propanol.

A method is also provided for making (S)- or(R)-1-(4-nitrophenoxy)3-3,4-dichlorophenylethylamino)-2-propanolcomprising reacting p-nitrophenyl ether with 3,4-dichirophenylethylamineto form said (S)- or(R)-1-(4-nitrophenoxy)3-(3,4-dichlorophenylethylamino)-2-propanol.

The remaining NMDA-receptor blockers which are derivatives of andrelated compounds to those described above may be synthesized, as willbe appreciated by those of skill in the art, by methods analogous tothose described herein.

DETAILED DESCRIPTION

The term “alkyl” takes its usual meaning in the art and is intended toinclude straight-chain, branched and cycloalkyl groups. The termincludes, but is not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl,2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl,n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2-ethylbutyl,1-ethylbutyl, 1,3-dimethylbutyl, n-heptyl, 5-methylhexyl, 4-methylhexyl,3-methylhexyl, 2-methylhexyl, 1-methylhexyl, 3-ethylpentyl,2-ethylpentyl, 1-ethylpentyl, 4,4-dimethylpentyl, 3,3-dimethylpentyl,2,2-dimethylpentyl, 1,1-dimethylpentyl, n-octyl, 6-methylheptyl,5-methylheptyl, 4-methylheptyl, 3-methylheptyl, 2-methylheptyl,1-methylheptyl, 1-ethylhexyl, 1-propylpentyl, 3-ethylhexyl,5,5-dimethylhexyl, 4,4-dimethylhexyl, 2,2-diethylbutyl,3,3-diethylbutyl, and 1-methyl-1-propylbutyl. Alkyl groups areoptionally substituted. Lower alkyl groups include among others methyl,ethyl, n-propyl, and isoprophyl groups. Lower alkyl groups as referredto herein have one to six carbon atoms.

The term “bulky ring-containing group” refers to a group containing 1 ormore ring structures which may be aryl rings or cycloalkyl rings.

The term “cycloalkyl” refers to alkyl groups having a hydrocarbon ring,particularly to those having rings of 3 to 7 carbon atoms. Cycloalkygroups include those with alkyl group substitution on the ring.Cycloalkyl groups can include straight-chain and branched-chainportions. Cycloalkyl groups include but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, andcyclononyl. Cycloalkyl groups can optionally be substituted.

The term “aryl” is used herein generally to refer to aromatic groupswhich have at least one ring having a conjugated pi electron system andincludes without limitation carbocyclic aryl, aralkyl, heterocyclicaryl, biaryl groups and heterocyclic biaryl, all of which can beoptionally substituted. Preferred aryl groups have one or two aromaticrings.

Substitution of alkyl groups includes substitution at one or morecarbons in the group by moieties containing heteroatoms. Suitablesubstituents for these groups include but are not limited to OH, SH,NH₂, COH, CO₂H, ORc, SRc, NRc Rd, CONRc Rd, and halogens, particularlyfluorines where Rc and Rd, independently, are alkyl, unsaturated alkylor aryl groups. Preferred alkyl and unsaturated alkyl groups are loweralkyl, alkenyl or alkynyl groups having from 1 to about 3 carbon atoms.

“Aralkyl” refers to an alkyl group substituted with an aryl group.Suitable aralkyl groups include among others benzyl, phenethyl andpicolyl, and may be optionally substituted. Aralkyl groups include thosewith heterocyclic and carbocyclic aromatic moieties.

“Heterocyclic aryl groups” refers to groups having at least oneheterocyclic aromatic ring with from 1 to 3 heteroatoms in the ring, theremainder being carbon atoms. Suitable heteroatoms include withoutlimitation oxygen, sulfur, and nitrogen. Heterocyclic aryl groupsinclude among others furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolo, pyrimidyl, pyrazinyl, imidazolyl, benzofuranyl, quinolinyl, andindolyl, all optionally substituted.

“Heterocyclic biaryl” refers to heterocyclic aryls in which a phenylgroup is substituted by a heterocyclic aryl group ortho, meta or para tothe point of attachment of the phenyl ring to the decalin orcyclohexane. Para or meta substitution is preferred. Heterocyclic biarylincludes among others groups which have a phenyl group substituted witha heterocyclic aromatic ring. The aromatic rings in the heterocyclicbiaryl group can be optionally substituted.

“Biaryl” refers to carbocyclic aryl groups in which a phenyl group issubstituted by a carbocyclic aryl group ortho, meta or para to the pointof attachment of the phenyl ring to the decalin or cyclohexane. Biarylgroups include among others a first phenyl group substituted with asecond phenyl ring ortho, meta or para to the point of attachment of thefirst phenyl ring to the decalin or cyclohexane structure. Parasubstitution is preferred. The aromatic rings in the biaryl group can beoptionally substituted.

Aryl group substitution includes substitutions by non-aryl groups(excluding H) at one or more carbons or where possible at one or moreheteroatoms in aromatic rings in the aryl group. Unsubstituted aryl, incontrast, refers to aryl groups in which the aromatic ring carbons areall substituted with H, e.g. unsubstituted phenyl(—C₆ H₅), ornaphthyl(—C₁₀H₇). Suitable substituents for aryl groups include amongothers alkyl groups, unsaturated alkyl groups, halogens, OH, SH, NH₂,COH, CO₂ H, ORe, SRe, NRe Rf, CONRe Rf, where Re and Rf independentlyare alkyl, unsaturated alkyl or aryl groups. Preferred substituents areOH, SH, ORe, and SRe where Re is a lower alkyl, i.e. an alkyl grouphaving from 1 to about 3 carbon atoms. Other preferred substituents arehalogens, more preferably fluorine, and lower alkyl and unsaturatedlower alkyl groups having from 1 to about 3 carbon atoms. Substituentsinclude bridging groups between aromatic rings in the aryl group, suchas —CO₂—, —CO—, —O—, —S—, —NH—, —CHCH— and —(CH₂)₁— where 1 is aninteger from 1 to about 5, and particularly —CH₂—. Examples of arylgroups having bridging substituents include phenylbenzoate, Substituentsalso include moieties, such as —(CH₂)₁—, —O—(CH₂)¹— or —OCO—(CH₂)₁—,where 1 is an integer from about 2 to 7, as appropriate for the moiety,which bridge two ring atoms in a single aromatic ring as, for example,in a 1, 2, 3, 4-tetrahydronaphthalene group. Alkyl and unsaturated alkylsubstituents of aryl groups can in turn optionally be substituted asdescribed supra for substituted alkyl and unsaturated alkyl groups.

The compounds of Formula I and their salts, as herein described, can beincorporated into standard pharmaceutical dosage forms, for example, fororal or parenteral application with the usual pharmaceutical adjuvantmaterials, for example, organic or inorganic inert carrier materials,such as, water, gelatin, lactose starch, magnesium stearate, talc,vegetable oils, gums, polyalkylene-glycols and the like. Carriers whichdo not consist of water or water and buffer alone are also contemplatedin this invention. The pharmaceutical preparations can be employed in asolid form, for example, as tablets, suppositories, capsules, or inliquid form, for example, as solutions, suspensions or emulsions.Pharmaceutical adjuvant materials can be added and include preservativesstabilizers, wetting or emulsifying agents, salts to change the osmoticpressure or to act as buffers. The pharmaceutical preparations can alsocontain other therapeutically active substances. Thus part of thisinvention is a pharmaceutical composition comprising a compound ofFormula I, in particular a preferred compound as described above, or apharmaceutically acceptable salt thereof and an inert carrier.

The dosage of the compounds referred to herein can vary within widelimits and will, of course, be fitted to the individual requirements ineach particular case. In the case of oral administration the dosage liesin the range of about 0.1 mg per dosage to about 1000 mg per day of acompound of formula I although the upper limit can also be exceeded whenthis is shown to be indicated. An amount effective to alleviate theneurodegeneration depends on the individual, however alleviation occurswhen the condition in question exhibits either symptomatic improvementor improvement according to an accepted assay. For the compounds hereinhaving enhanced activity at pH lower than normal, dosages of thesecompounds for use in the methods of this invention involvingadministration to a patient having lower-than-normal brain-tissue pH,are less than normal dosage amounts for similar compounds not havingsuch enhanced activity at lowered pH. When used to treat stroke or othertraumatic ischemic events, the treatment should be administered prior orto or immediately after the event.

Lowered pH due to pathological conditions is between about 6.4 and about7.2, generally about 6.9. Normal brain-tissue pH is between about 7.2and about 7.6, generally about 7.4.

EXAMPLES

The following examples illustrate the present invention in more detail.However, they are not intended to limit its scope in any manner.

Example 1 NMDA Receptor Block in Xenopus oocytes by Novel Compounds

Current recordings were obtained using two electrode voltage clamp ofXenopus oocytes injected with cRNA encoding the NR1-1a and NR2B NMDAreceptor subunits. Cells were injected with 5-15 ng of cRNA encodingNR1-1a in combination with a 2-3 fold greater amount of either NR₂BcRNA. Injected oocytes were maintained at 17° C. in Barths solutioncontaining penicillin (10 U/ml) and streptomycin (10 μg/ml) for 2-6days, after which recordings were made at room temperature from oocytescontinuously perfused in a standard frog Ringers solution. This solutionwas composed of (in MM): 90 NaCl, 1.0 KCl, 10 Hepes and 0.5 BaCl₂.Recording pipettes were filled with 0.3M KCl. Saturating concentrationsof glutamate (20-50 μM) and glycine (20 μM) were used to activate thereceptor. Drugs were prepared daily from frozen stock solutions in DMSO.Glutamatelglycine-activated currents were typically elicited from aholding potential of −20 to −40 mV. Current signals were digitized andanalyzed using custom acquisition software. To study the effects of pH,oocytes were perfused with Ringer's solution at the desired pH until astable baseline had been reached before subsequent agonist application.

Application of glutamate and glycine produced a stable, rapidly-risingand nondesensitizing current in the majority of oocytes. Oocytes inwhich the glutamate/glycine current was not stable or in which thebaseline holding current drifted were discarded. Inhibition of theglutamate/glycine current by drugs was examined by applying 1-4different concentrations of the antagonist to each oocyte. The amplitudeof the glutamate/glycine current at each concentration of antagonist wasexpressed as a percentage of the control glutamate/glycine current inthe absence of antagonist, and IC50's were determined by fitting thelogistic equation to the data (n=3-46 oocytes per condition). On averagerecordings were made from 14 oocytes per condition. The fold potencyboost was calculated as the ratio of the experimental IC50 valuesdetermined at pH 7.6 and 6.9 (IC50 at pH 7.6/IC50 at pH 6.9).

TABLE A Novel NMDA receptor inhibitors with potency boosts >5-fold forchanges from pH 7.6 to pH 6.9

Racemic mixtures were studied when stereochemistry is not indicated. Thefold- decrease in IC50 as a function of pH for antagonists ofNR1-1a/NR2B receptors was measured in Xenopus oocytes as describedabove. All compounds were more potent at pH 6.9. Fold increase inpotency IC50 at pH 6.9 between pH R1 R2 R3 R4 R5 (μM) 7.6 and 6.9 NovelCompounds 93-31 (S) Cl H n-butyl OH Me 0.058 51.2 93-29 (S) Cl H H OHphenyl 1.160 18.0 93-24 H Cl H OH Me 1.360 11.8 93-1 (R) Cl H Methyl OHMe 0.085 11.3 93-8 (S) Cl H EtOH OH Me 0.029 11.3 93-28 (S) Cl H COCH₃OCOCH₃ Me 1.638 11.1 93-5 (S) Cl H Ethyl OH Me 0.020 8.00 93-30 (S) Cl Hbenzyl OH Me 0.070 16.8 93-6 (S) Cl H n-propyl OH Me 0.111 6.54 93-2 (S)Cl H Methyl OH Me 0.063 5.87 Known compounds Haloperidol — — — — — 0.8116.5

TABLE B Novel NMDA receptor inhibitors with pH potency boosts <5 foldfor changes from pH 7.6 to pH 6.9

Racemic mixtures were studied when stereochemistry is not indicated. Thefold decrease in IC50 as a function of pH for antagonists of NR1-1a/NR2Breceptors was measured in Xenopus oocytes as described above. Foldincrease in potency IC50 at pH 6.9 between pH R1 R2 R3 (μM) 7.6 and 6.9Novel compound 93-34 (S) meta-F-benzyl H NHSO₂Me 0.210 4.62 93-35 (S)ortho-F-benzyl H NHSO₂Me 0.048 3.60 93-4 (S) H H NHSO₂Me 0.026 3.54 93-3(R) H H NHSO₂Me 0.099 3.26 93-14 H H OCH₃ 19.900 2.01 93-27 (S)

R1 = R2 NHSO₂Me 0.338 0.95 93-33 (S) para-F-benzyl H NHSO₂Me 0.520 0.810Known compounds Ifenprodil — — — 0.068 2.66 Ro256981 — — — 0.018 0.444

TABLE C Importance of chain N ionization on potency boost at low pH forNMDA receptor inhibitors.

All compounds shown are assumed to be novel. Compounds with pKa valuesfor the chain nitrogen between 9 and 5 undergo changes in theconcentration of the ionized species over the range of pH values tested(6.9-7.6). Compounds with reduced pKa values show larger increases inionization at pH 6.9 compared to pH 7.6. We found a significantcorrelation (R = −0.98) between the potency boost and pKa of the chainnitrogen for the following series of compounds (n-butyl was omittedbecause other features of the molecule dominate the potency boost).Molecules with no ionization at this nitrogen showed no pH dependentpotency boost. For each compound, the pKa of the amine group in thelinker chain was calculated by the web-based pKa calculator from ACDLabs(www.acdlabs.com). The fold decrease in IC50 as a function of pH forantagonist of NR1-1a/NR2B receptors was measured in Xenopus oocytes asdescribed above. Fold increase in potency pKa of the between pH R1 R2chain amine 7.6 and 6.9 Compounds with ionization of N changing betweenpH 6.9 and 7.6 93-4 (S) H H 8.36 3.54 93-6 (S) n-Propyl H 8.11 6.54 93-5(S) Ethyl H 8.11 8.00 93-31 (S) n-Butyl H 8.11 51.2 93-2 (S) Me H 8.035.87 93-8 (S) EtOH H 7.57 11.3 93-30 (S) Benzyl H 7.08 16.8 Compoundwith an unionized nitrogen at both pH 6.9 and 7.6 93-27 (S)

R1 = R2 <1 0.954

TABLE D Importance of the NHSO₂-Me constituent on the phenyl ring forNMDA receptor inhibitors.

All compounds shown are assumed to be novel. Racemic mixtures werestudied when stereochemistry is not indicated. Values not determined areindicated as N.D. The fold decrease in IC50 as a function of pH forantagonists of NR1-1a/NR2B receptors was measured in Xenopus oocytes asdescribed above. All compounds were more potent at pH 6.9. Fold increasein IC50 at potency Com- pH 6.9 between pH pound R1 R2 R3 (μM) 7.6 and6.9 93-4 (S) H H NHSO₂- 0.026 3.54 Me 93-9 (S) H NHSO₂- H 0.208 8.19 Me93-32 (S) NHSO₂- H H 17.9 N.D. Me 93-7 (S) H H N(CH₃)SO₂- 2.33 5.51 Me93-29 (S) H H NHSO₂- 1.16 18.02 phenyl 93-10 (S) H H NO₂ 12.1 1.60 93-14H H OCH₃ 19.9 2.01 93-16 H H OCF₃ 11.2 4.82

TABLE E Anticonvulsant effect Delay Control tonic from drug hindlimbinjection to extension Dose electroshock (THE) time THE in drug Drug(mg/kg) (min) (sec) (% control) Vehicle 0 15 8.5 ± 0.3  102 ± 3.1Carbamazepine 40 30 8.5 ± 0.3  0.0 ± 0.0 93 10 15 8.5 ± 0.4 78.2 ± 4.593 10 30 8.8 ± 0.2 58.5 ± 11.3* 93 10 60 9.0 ± 0.2 62.4 ± 3.9* 93 30 2407.4 ± 0.3 96.2 ± 1.7 93-4 3 15 7.2 ± 0.2 91.1 ± 2.7 93-4 3 60 6.7 ± 0.6 109 ± 11.5 93-4 30 15 7.5 ± 0.2 66.6 ± 12.5* 93-4 30 60 6.6 ± 0.6 30.8± 12.1* 93-8 30 15 7.0 ± 0.4 91.9 ± 0.4 93-8 30 30 7.4 ± 0.2 85.7 ± 2.893-8 30 60 7.7 ± 0.4 59.3 ± 4.1* 93-27 30 15 7.4 ± 0.31 97.0 ± 0.6 93-2730 30 8.1 ± 0.5 95.6 ± 1.3 93-27 30 60 7.5 ± 0.2 89.7 ± 0.8

Anticonvulsive effects of (R,S)1-(4-methanesulfonamidophenoxy)-3-(N-methyl-3,4-dichlorophenylethylamine)-2-propanolhydrochloride (AM92016) [Compound 93],(S)-1-(4-methanesulfonamideophenoxy)-3-(3,4-dichlorophenylethylamine)-2-propanolhydrochloride [Compound 93-4] and(S)-1-(4-methanesulphonamidephenoxy)-e-(N-(2-hydroxyethyl)-3,4-dichlorophenylethylamino)-2-propanol[Compound 93-8], but not(S)-1-(4-methanesulphonamideophenoxy)-3-(N-acetyl-3,4-dichlorophenylethylamino)-2-propylacetate[compound 93-27] were shown.

Methods: Male Sprague-Dawley rats weighing less than 150 gm were usedfor these experiments. Maximal electroshock seizures were produced bydelivering 200 ms biphasic square-wave pulses of 200 mA at 60 Hz viacorneal electrodes, using a Wahlquist Constant Current Source (Salt LakeCity, Utah). A drop of 0.9% lidocaine in saline was applied to eachcornea 30 s before stimulus delivery to minimize pain. Automatic timersrecorded the durations of-tonic hindlimb flexion, tonic hindlimbextension (THE), clonus and flaccidity that sequentially followedstimulus delivery. The duration of THE was used as an index of seizureseverity. Animals were stimulated on three consecutive days, referred toas “control”, “test”, and “recovery”. A minimum control THE duration of4 s was used as a criterion for inclusion in subsequent testing; 90% ofanimals screened had a control THE duration greater than 4 s. On “test”day, each animal received either vehicle or drug at varying intervalsprior to stimulation. Reversibility of drug effect on THE wasascertained by response to stimulation administered one day after the“test” session. The values shown in the table are the mean (± sem) THEduration in the test condition, as a percentage of the mean of controland recovery conditions. Four rats were used for each time point.

-   -   P<0.001 for difference from vehicle by one-way ANOVA with        Dunnett's post hoc test. For all other conditions P>0.05.

Example 2 Synthetic Methods

Compounds implied by the following general formula and given in Table 1are representative.

TABLE 1

Compound R₁ R₂ R₃ 4 CH₃ H 4-NHSO₂CH₃ 5 H H 4-NHSO₂CH₃ 6 C₂H₅ H4-NHSO₂CH₃ 7 C₂H₄—OH H 4-NHSO₂CH₃ 8 C₃H₇ H 4-NHSO₂CH₃ 9 C₄H₉ H4-NHSO₂CH₃ 10 Benzyl H 4-NHSO₂CH₃ 11 2-Fluorobenzyl H 4-NHSO₂CH₃ 123-Fluorobenzyl H 4-NHSO₂CH₃ 13 4-Fluorobenzyl H 4-NHSO₂CH₃ 142,6-Difluorobenzyl H 4-NHSO₂CH₃ 15 2,3,4-Trifluorobenzyl H 4-NHSO₂CH₃ 16H H 3-NHSO₂CH₃ 17 H H 2-NHSO₂CH₃ 18 acetyl acetyl 4-NHSO₂CH₃ 19

4-NHSO₂CH₃ 20 H H 4-N(CH₃)SO₂CH₃ 21 H H 4-NHSO₂Ph 22 H H 4-NO₂

Synthesis of the above series is exemplified by 4 and 5 as shown inScheme 1.

Spectroscopic and Purity Determinations. The ¹H-NMR and ¹³C-NMR spectrawere recorded on a Varian Inova-400 (400 MHz) spectrometer. HPLCanalyses were performed on a Schimadzu LC-10A system equipped with aSPD-10A UV detector. Enantiomeric excesses were determined by HPLC on aChiralcel OD column using a Hexane-ethanol 90:10 solvent system.Hydrogenations were performed using the baloon technique in a two-neckedflask.

Syntheses: All the reactions were performed under anhydrous nitrogenatmosphere in oven-dried glassware.

Preparation of (S)-Glycidyl p-Nitrophenyl Ether (1-S)

p-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF andcesium fluoride (3.02 g, 19.9 mmol) was added. The reaction mixture wasstirred for 1 hour at room temperature and (S)-Glycidyl nosylate (1.71g, 6.6 mmol) was added. The system was stirred for an additional 24hours at room temperature. Water (150 ml) was added, and the solutionwas extracted with ethylacetate. The organic phase was dried over MgSO₄and evaporated. The residue was purified with column chromatograph usingethylacetate:hexane (50:50) solvent system to give (S)-Glycidylp-nitrophenyl ether (99.6% ee, based on chiral HPLC with Chiralcel OD,m.p 78-9° C.) as a yellowish solid (1.21 g, 93% yield). The NMR valuesare the same as the literature values for the racemic mixture: ¹H-NMR(CDCl₃) δ 2.78 (dd, 1H), 2.95 (t 1H), 3.39 (m 1H), 4.0 (dd, 1H), 4.38(dd, 1H), 6.99 (dd, 2H), 8.2 (dd, 2H).

The (R)-enantiomer of compound 1, starting with (R)-Glycidyl nosylate(1-R) was prepared similarly: ¹H-NMR (CDCl₃) δ 2.79 (dd, 1H), 2.95 (t1H), 3.4 (m 1H), 4.0 (dd, 1H), 4.39 (dd, 1H), 7.00 (dd, 2H), 8.2 (dd,2H).

Preparation of Palladium-on-Carbon Ethylenediamine Complex as a ReducingAgent

Palladium on activated carbon (5%, w/w, 0.2 g) was tared in athree-necked baloon flask. Then, ethylenediamine (0.42 g, 0.1 M) in 70ml anhydrous methanol was added to the Pd/C under an argon atmosphere.The reaction mixture was stirred for 32 hours under argon. The catalystwas filtered and washed with methanol and ether, then dried for 24 hoursunder high vacuum pumping.

Preparation of (S)-Glycidyl p-Aminophenyl Ether (2-S

Compound 1 (0.5 g, 2.6 mmol) and 5% Pd/C(en) (10% of the weight ofstarting material) in 5 ml anhydrous THF was hydrogenated at ambientpressure and temperature for 3-5 hours. The reaction mixture wasfiltered through a membrane filter (13, 0.22 μm) and the filtrate wasconcentrated in vacuo. The compound was obtained as a crude mixture ofproducts arising from nitro group reduction and epoxide ring opening.Isolation of the desired compound was difficult because of the labilityof the components of the mixture on silica gel. The product ratio fromNO₂ reduction and ring opening (94:6) was determined by integrating theepoxide-ring protons in the reduced compound and the methyl proton inthe ring opened compound (98% total yield for the mixture). The NMRsignals for 2-S are the same as reported in the literature.

¹H-NMR (CDCl₃) δ 2.69 (dd, 1H), 2.83 (t, 1H), 3.26-3.30 (m 1H), 3.43(brs, 2H), 3.83 (dd, 1H), 4.1 (dd, 1H), 6.59 (dd, 2H), 6.72 (dd, 2H).

The (R)-enantiomer of compound 2 (2-R) was also prepared from compound1-R. ¹H-NMR (CDCl₃) δ 2.69 (dd, 1H), 2.83 (t, 1H), 3.26-3.30 (m 1H),3.43 (brs, 2H), 3.83 (dd, 1H), 4.1 (dd, 1H), 6.59 (dd, 2H), 6.72 (dd,2H).

Preparation of (S)-Glycidyl N-Methylsulfonyl-p-Aminophenyl Ether (3-S)

Compound 2-S (0.4 g, 2.4 mmol) dissolved in 20 ml anhydrous DCM andN,N-diisopropyl-N-ethylamine (0.45 ml, 2.6 mmol) were combined at 0° C.After stirring the latter mixture for 15 minutes, methanesulfonylchloride (0.2 ml, 2.6 mmol) was added dropwise at 0° C. After stirringover night, the reaction was extracted with water and washed with brine.The organic phase was dried over magnesium sulfate and evaporated. Thenon-volatile residue was purified with flash chromatography using ethylacetate: DCM (30:70) solvent to give a white solid (m.p: 106-108° C.,70% yield).

¹H-NMR (CDCl₃) δ 2.77 (dd, 1H), 2.92 (t, 1H), 2.95 (s, 3H), 3.34-3.36 (m1H), 3.92 (dd, 1H), 4.24 (dd, 1H), 6.34 (s, 1H), 6.91 (dd, 2H), 7.19(dd, 2H).

The (R)-enantiomer of compound 3 (3-R) was also prepared starting withcompound 2-R. ¹H-NMR (CDCl₃) δ 2.76 (dd, 1H), 2.92 (t, 1H), 2.95 (s,3H), 3.34-3.36 (m 1H), 3.92 (dd, 1H), 4.24 (dd, 1H), 6.36 (s, 1H), 6.91(dd, 2H), 7.19 (dd, 2H).

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)3-(N-methyl-3,4-dichlorophenylethylamino)-2-propanol(4-S)

Compound 3-S (0.326 g, 1.34 mmol) andN-methyl-3,4-dichloropenylethylamine (0.276 g, 1.34 mmol) were dissolvedin 5 ml ethanol and refluxed for 20 hours. The solvent was thenevaporated and the residue purified by flash chromatography usingdichloromethane: methanol (90:10) solvent to give the product as acolorless oil (30% yield).

¹H-NMR (CDCl₃) δ 2.37 (s, 3H), 2.52-2.78 (m, 6H), 2.93 (s, 3H), 3.91,(dd, Hα, 1H), 3.92 (s, Hβ, !H), 3.98-4.04 (m, 1H), 6.86 (dd, 2H), 7.01(dd, 1H), 7.17 (dd, 2H), 7.28 (d, 1H), 7.33 (d, 1H).

Compound 4-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid which complexes with 1 mol ofwater. Anal. Calcd for C₁₉H₂₄N₂O₄SCl₂.HCl.1H₂O: C, 45.47; H 5.42; N,5.58. Found: C, 43.87; H 5.41; N, 4.94.

The (R)-enantiomer of compound 4 (4-R) was also prepared from compound3-R.

¹H-NMR (CDCl₃) δ 2.37 (s, 3H), 2.52-2.78 (m, 6H), 2.93 (s, 3H), 3.91,(dd, Hα, 1H), 3.92 (s, Hβ, !H), 3.98-4.04 (m, 1H), 6.86 (dd, 2H), 7.01(dd, 1H), 7.17 (dd, 2H), 7.28 (d, 1H), 7.33 (d, 1H).

Compound 4-R was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid which complexes with 1 mol ofwater. Anal. Calcd for C₁₉H₂₄N₂O₄SCl₂.HCl.1H₂O: C, 45.47; H 5.42; N,5.58. Found: C, 43.80; H 5.45; N, 5.27.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(3,4-dichlorophenylethylamino)-2-propanol(5-S)

Compound 3-S (0.364 g, 1.5 mmol) and 3,4-dichloropenylethylamine (0.284g, 0.11 ml, 1.5 mmol) were dissolved in 5 ml ethanol and refluxed for 5hours. The solvent was evaporated and the non-volatile residue purifiedby flash chromatography using dichloromethane: methanol (90:10) solventto give the product as a colorless oil (80% yield). ¹H-NMR (CDCl₃) δ2.75-2.93 (m, 6H), 2.95 (s, 3H), 3.94, (dd, Hα, 1H), 3.96 (s, Hβ, 1H),4.00-4.05 (m, 1H), 6.86 (dd, 2H), 7.04 (dd, 1H), 7.17 (dd, 2H), 7.30 (d,1H), 7.35 (d, 1H).

Compound 5-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid. Anal. Calcd forC₁₈H₂₂N₂O₄SCl₂.HCl: C, 46.02; H 4.93; N, 5.96. Found: C, 46.44; H 4.95;N, 5.78.

The (R)-enantiomer of compound 5 (5-R) was also prepared from compound4-R.

¹H-NMR (CDCl₃) δ 2.75-2.94 (m, 6H), 2.95 (s, 3H), 3.94, (dd, Hα, 1H),3.96 (s, Hβ, 1H), 3.99-4.05 (m, 1H), 6.87 (dd, 2H), 7.04 (dd, 1H), 7.18(dd, 2H), 7.30 (d, 1H), 7.35 (d, 1H).

Compound 5-R was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid. Anal. Calcd forC₁₈H₂₂N₂O₄SCl₂.HCl: C, 46.02; H 4.93; N, 5.96. Found: C, 46.29; H 5.06;N, 5.84.

The general reactions for the synthesis of representative compounds 6and 8-15 are given in Scheme 2. The corresponding substituents arelisted in Table 2.

TABLE 2 Substitutents representing both S- and R-enantiomers Compound R6 CH₃ 8 C₂H₅ 9 C₃H₇ 10 Phenyl 11 2-Fluorophenyl 12 3-Fluorophenyl 134-Fluorophenyl 14 2,6-Difluorophenyl 15 2,3,4-TrifluorophenylGeneral Method for preparation of compounds 6, 8-15.

Compound 5 (1 mmol) and the appropriate aldehyde (1 mmol) were dissolvedin 10 ml 1,2-dichloroethane and treated with sodiumtriacetoxyborohydride (1.4 mmol). After stirring overnight at roomtemperature, the reaction mixture was quenched with saturated sodiumbicarbonate. The water phase was extracted with 1,2-dichloroethane; theorganic phase was dried over MgSO₄ and evaporated. The residue waspurified with flash chromatography to give a colorless oil.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-ethyl-3,4-dichlorophenylethylamino)-2-propanol(6-S)

72% yield, solvent for flash chromatography DCM:MeOH (90:10). ¹H-NMR(CDCl₃) δ 1.03 (t, 3H), 2.58-2.80 (m, 8H), 2.91 (s, 3H), 3.88, (dd, Hα,1H), 3.90 (s, Hβ, 1H), 3.94-3.96 (m, 1H), 6.83 (dd, 2H), 6.99 (dd, 1H),7.16 (dd, 2H), 7.25 (d, 1H), 7.31 (d, 1H).

Compound 6-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid which which complexes with 1 molof water.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)3-(N-propyl-3,4-dichlorophenylethylamino)-2-propanol(8-S)

80% yield, solvent for flash chromatography DCM:MeOH (90:10). ¹H-NMR(CDCl₃) δ 0.86 (t, 3H), 1.39-1.56 (m, 2H), 2.56-2.82 (m, 8H), 2.91 (s,3H), 3.89, (dd, Hα, 1H), 3.90 (s, Hβ, 1H), 3.92-3.96 (m, 1H), 6.84 (dd,2H), 6.99 (dd, 1H), 7.16 (dd, 2H), 7.25 (d, 1H), 7.31 (d, 1H).

Compound 8-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid which which complexes with 1 molof water.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-butyl-3,4-dichlorophenylethylamino)-2-propanol(9-S)

74% yield, solvent for flash chromatography DCM:MeOH (90:10). ¹H-NMR(CDCl₃) δ 0.88 (t, 3H), 1.22-1.30 (m, 2H), 1.36-1.45 (m, 2H), 2.44-2.80(m, 8H), 2.89 (s, 3H), 3.88, (dd, Hα, 1H), 3.89 (s, Hβ, 1H), 3.92-3.96(m, 1H), 6.82 (dd, 2H), 6.98 (dd, 1H), 7.16 (dd, 2H), 7.24 (d, 1H), 7.29(d, 1H).

Compound 9-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-benzyl-3,4-dichlorophenylethylamino)-2-propanol(10-S)

70% yield, solvent for flash chroma-tography DCM:MeOH (90:10). ¹H-NMR(CDCl₃) δ 2.62-2.84 (m, 6H), 2.91 (s, 3H), 3.57 (d, 1H), 3.79 (d, 1H),3.84, (d, Hα, 1H), 3.86 (s, Hβ, 1H), 3.92-4.08 (m, 1H), 6.80 (dd, 2H),6.92 (dd, 1H), 7.15 (dd, 2H), 7.19 (d, 1H), 7.24-7.36 (m, 6H).

Compound 10-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid which which complexes with 1 molof water.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-(2-fluorobenzyl)-3,4-dichlorophenylethylamino)-2-propanol(11-S)

65% yield, solvent for flash chromatography DCM:EtOAc (70:30). ¹H-NMR(CDCl₃) δ 2.69-2.88 (m, 6H), 2.93 (s, 3H), 3.68 (d, 1H), 3.81 (d, 1H),3.88, (d, Hα, 1H), 3.89 (s, Hβ, 1H), 4.01-4.06 (m, 1H), 6.83 (dd, 2H),6.91 (dd, 1H), 7.08 (dd, 2H), 7.14-7.20 (m, 3H), 7.22-7.29 (m, 3H).

Compound 11-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid which which complexes with 1 molof water.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-(3-fluorobenzyl)-3,4-dichlorophenylethylamino)-2-propanol(12-S)

85% yield, solvent for flash chro-matography DCM:EtOAc (70:30). ¹H-NMR(CDCl₃) δ 2.69-2.88 (m, 6H), 2.94 (s, 3H), 3.59 (d, 1H), 3.78 (d, 1H),3.86, (d, Hα, 1H), 3.88 (s, Hβ, 1H), 3.98-4.03 (m, 1H), 6.83 (dd, 2H),6.93 (dd, 1H), 7.17 (dd, 2H), 7.16-7.21 (m, 3H), 7.24-7.32 (m, 3H).

Compound 12-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid which which complexes with 1 molof water.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-(4-fluorobenzyl)-3,4-dichlorophenylethylamino)-2-propanol(13-S)

80% yield, solvent for flash chro-matography DCM:EtOAc (70:30). ¹H-NMR(CDCl₃) δ 2.67-2.86 (m, 6H), 2.94 (s, 3H), 3.55 (d, 1H), 3.76 (d, 1H),3.85, (d, Hα, 1H), 3.87 (s, Hβ, 1H), 3.97-4.03 (m, 1 H), 6.82 (dd, 2H),6.92 (dd, 1H), 6.97 (dd, 2H), 7.14-7.20 (m, 5H), 7.29 (d, 1H).

Compound 13-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid which which complexes with 1 molof water.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-(2,6-difluorobenzyl)-3,4-dichlorophenylethylamino)-2-propanol(14-S)

60% yield, solvent system for flash chromatography DCM:EtOAc (70:30).¹H-NMR (CDCl₃) δ 2.67-2.81 (m, 6H), 2.94 (s, 3H), 3.77 (d, 1H), 3.85 (d,1H), 3.89, (d, Hα, 1H), 3.90 (s, Hβ, 1H), 4.02-4.09 (m, 1H), 6.85 (dd,2H), 6.86 (s, 1H), 6.92 (dd, 2H), 7.15 (dd, 2H), 7.17 (d, 1H), 7.25 (dd,2H).

Compound 14-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-(2,3,4-trifluorobenzyl)-3,4-dichlorophenylethylamino)-2-propanol (15-S)

65% yield, solvent for flash chromatography DCM:EtOAc (70:30). ¹H-NMR(CDCl₃) δ 2.65-2.80 (m, 6H), 2.95 (s, 3H), 3.68 (d, 1H), 3.78 (d, 1H),3.87, (d, Hα, 1H), 3.89 (s, Hβ, 1H), 4.00-4.04 (m, 1H), 6.83 (dd, 1H),6.88-6.95 (m, 3H), 7.16 (dd, 2H), 7.18 (dd, 2H), 7.30 (dd, 1H).

Compound 15-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-(2,3,4,5,6-pentafluoro-benzyl)-3,4-dichlorophenylethylamino)-2-propanol(16-S)

40% yield, solvent for flash chromatography DCM:EtOAc (70:30). ¹H-NMR(CDCl₃) δ 2.58-2.79 (m, 6H), 2.93 (s, 3H), 3.41 (dd, 1H), 3.61 (dd, 1H),4.08(d, 2H), 4.50-4.60 (m, 1H), 6.87-6.93 (m, 3H), 7.00(d, 1H), 7.15(d,1H), 7.19 (dd, 2H).

Compound 7 was prepared in two steps as shown in scheme 3.

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-(2-butyroxyethyl)-3,4-dichlorophenylethylamino)-2-propanol(7a-S)

With the general method, O-Butyryl glycoaldehyde and compound S gave the(S)-1-(4-Methanesulphonamidephenoxy)3-(N-(2-butyroxyethyl)-3,4-dichlorophenylethylamino)-2-propanolin 85% yield as a colorless oil. This compound was purified with flashchromatography using DCM: Ethyl acetate (70:30) solvent.

¹H-NMR (CDCl₃) δ 0.89 (t, 3H), 1.56-1.64 (m, 2H), 2.24 (t, 2H),2.64-2.87 (m, 6H), 2.90 (s, 3H), 3.87-4.13 (m, 6H), 4.38-4.44 (m, 1 H),6.83 (dd, 2H), 6.99 (dd, 1H), 7.16 (dd, 2H), 7.25 (dd, 1H), 7.31 (d,1H).

Preparation of(S)-1-(4-Methanesulphonamidephenoxy)-3-(N-(2-hydroxyethyl)-3,4-dichlorophenylethylamino)-2-propanol(7-S)

Reaction of compound 7a-S with sodium methoxide (2 equiv) gave compound7-S in 75% yield as a colorless oil. This compound was purified withflash chromatography using DCM:MeOH (90:10) solvent.

¹H-NMR (CDCl₃) δ 2.72-2.86 (m, 8H), 2.94 (s, 3H), 3.64, (dt, 2H), 3.87(s, Hβ, 1H), 3.89 (dd, Hα, 1H), 3.98-4.04 (m, 1H), 6.84 (dd, 2H), 7.03(dd, 1H), 7.17 (dd, 2H), 7.29 (d, 1H), 7.33 (d, 1H).

Compound 7-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid.

Synthesis of compound 16 is shown in Scheme 4.

Preparation of (S)-Glycidyl m-Nitrophenyl Ether (16a-S)

3-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF,and cesium fluoride (3.02 g, 19.9 mmol) was added. The reaction mixturewas stirred for 1 hour at room temperature, and (S)-glycidyl nosylate(1.71 g, 6.6 mmol) was added. The reaction mixture was stirred for 20hours at room temperature. Water (150 ml) was added, and the solutionwas extracted with ethylacetate. The organic phase was dried over MgSO₄and evaporated. The residue was purified with column chromatograph usingethylacetate:hexane (50:50) solvent to give (S)-glycidyl m-nitrophenylether (1.02 g 80% yield, m.p 44-5° C.) as a yellowish solid.

¹H-NMR (CDCl₃) δ 2.78 (dd, 1H), 2.95 (t 1H), 3.39 (m 1H), 4.0 (dd, 1H),4.38 (dd, 1H), 7.28 (dd, 1H), 7.41(q, 1H), 7.67-7.87(m, 2H).

Preparation of (S)-Glycidyl m-Aminophenyl Ether (16b-S)

Compound 16a-S (0.5 g, 2.6 mmol) and %5 Pd/C(en) (10% of the weight ofstarting material) in 5 ml anhydrous THF was hydrogenated at ambientpressure and temperature for 3-5 hours. The reaction mixture wasfiltered by using a membrane filter (13, 0.22 μm), and the filtrate wasconcentrated in vacuo. The resulting compound is a crude mixture ofnitro group reduction and epoxide ring opening. Isolation of the desiredcompound was difficult because of the lability of the components of themixture on silica gel. The product ratio of the NO₂ reduction and ringopening (80:20) was determined on the basis of the integration ratio ofthe epoxide-ring protons from nitro group reduction and the methylproton of the ring opened compound (98% total yield for the mixture).

¹H-NMR (CDCl₃) δ 2.69 (dd, 1H), 2.83 (dt, 1H), 3.27-3.32 (m 1H), 3.43(brs, 2H), 4.15 (dd, 1H), 4.27 (dd, 1H), 6.13-6.35 (m, 3H), 6.89-7.03(m, 1H).

Preparation of (S)-Glycidyl N-Methylsulfonyl-m-Aminophenyl Ether (16c-S)

Compound 16b-S (0.4 g, 2.4 mmol) dissolved in 20 ml anhydrous DCM, andN,N-diisopropyl-N-ethylamine (0.45 ml, 2.6 mmol) was added at 0° C..After stirring for 15 minutes, methanesulfonyl chloride (0.2 ml, 2.6mmol) was added to the reaction mixture at 0° C.. After stirringovernight, the reaction mixture was extracted with water and washed withbrine. The organic phase was dried and evaporated. The residue waspurified with flash chromatography using ethyl acetate:DCM (30:70)solvent to give a colorless oil (45% yield).

¹H-NMR (CDCl₃) δ 2.75 (dd, 1H), 2.89 (t, 1H), 2.99 (s, 3H), 3.33-3.36 (m1H), 3.88 (dd, 1H), 4.24 (dd, 1H), 6.70 (dd, 1H), 6.81 (dt, 1H),7.16-7.23 (m, 2H), 7.52 (s, 1H).

Preparation of(S)-1-(3-Methanesulphonamidephenoxy)3-(3,4-dichlorophenylethyl-amino)-2-propanol(16-S)

Compound 16c-S (0.364 g, 1.5 mmol) and 3,4-dichloropenylethylamine(0.284 g, 0.11 ml, 1.5 mmol) were dissolved in 5 ml ethanol and refluxedfor 10 hours. Then, solvent was evaporated and the residue purified byflash chromatography using dichloromethane: methanol (90: 10) solvent togive the product (55% yield).

¹H-NMR (CDCl₃) δ 2.75-2.95 (m, 6H), 3.01 (s, 3H), 3.96, (dd, Hα, 1H),3.97 (s, Hβ, 1H), 3.99-4.05 (m, 1H), 6.71 (dd, 1H), 6.75 (dd, 1H), 6.82(t, 1H), 7.05 (dd, 1H), 7.24 (d, 1H), 7.30 (d, 1H), 7.36 (d, 1H).

Compound 16-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid.

Compound 17-S was prepared as follows (Scheme 5).

Preparation of (S)-Glycidyl o-Nitrophenyl Ether (17a-S)

2-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF.Cesium fluoride (3.02 g, 19.9 mmol) was added to the reaction. Thereaction mixture was stirred for 1 hour at room temperature and(S)-glycidyl nosylate (1.71 g, 6.6 mmol) was added. The reaction wasstirred for 16 hours at room temperature. Water (150 ml) was added, andthe solution was extracted with ethylacetate. The organic phase wasdried over MgSO₄ and evaporated. The residue was purified with columnchromatograph using ethylacetate:hexane (50:50) solvent to give(S)-glycidyl o-nitrophenyl ether (1.21 g, 90% yield, m.p. 46-47° C.) asa white solid.

¹H-NMR (CDCl₃) δ 2.87 (dd, 1H), 2.92 (t 1H), 3.37-3.41 (m 1H), 4.14 (dd,1H), 4.40 (dd, 1H), 7.06 (dt, 1H), 7.12 (d, 1H), 7.53(dt, 1H), 7.84 (dd,1H).

Preparation of(S)-1-(2-nitrophenoxy)-3-(3,4-dichlorophenylethylamino)-2-propanol(17b-S)

Compound 17a-S (1.05 g, 5.4 mmol) and 3,4-dichloropenylethylamine (1.02g, 0.8 ml, 5.4 mmol) were dissolved in 25 ml ethanol and refluxed for 12hours. Then the solvent was evaporated and the residue recrystallizedfrom ethylacetate-petroleum ether to give the product (1.02 g, 99%yield, m.p. 73-74 ° C. ) as a white solid.

¹H-NMR (CDCl₃) δ 2.75-2.94 (m, 6H), 4.02-4.18 (m, 3H), 7.05 (dt, 3H),7.33 (dd, 2H), 7.53 (dt, 1H), 7.87 (dd, 1H).

Preparation of 2-phenyl-3-(N-phenylethylamino)-S-(4-nitrophenoxymethyl)oxazolidine (17c-S)

Compound 17b-S (1.02 g, 2.6 mmol), benzaldehyde (0.315 g, 0.3 ml, 2.96mmol), and p-toluene sulphonic acid (catalytic amount) were dissolved in50 ml of toluene and refluxed in a Dean Stark apparatus for 30 hours,cooled, and extracted with saturated sodium bicarbonate. The organiclayer was dried over MgSO₄ and evaporated yielding a yellow oil as amixture of stereoisomers. The material was used directly for the nextstep.

¹H-NMR (CDCl₃) δ 2.61-2.99 (m, 10H), 3.56 (dd, 1H), 3.61 (dd, 1H), 3.83(t, 1H), 4.03 (t, 1H), 4.20 (dd, 2H), 4.32 (dd, 2H), 4.544.58 (m, 1H),4.64-4.69 (m, 1H), 4.81 (s, 1H), 4.94 (s, 1H), 6.88 (dd, 1H), 6.93 (dd,1H), 7.04-7.21 (m, 6H), 7.26-7.43 (m, 12H), 7.51 (d, 1H), 7.55 (d, 1H),7.85 (dd, 1H), 7.88 (dd, 1H).

Preparation of 2-phenyl-3-(N-phenylethylamino)-5-(4-aminophenoxymethyl)oxazolidine (17d-S)

Compound 17c-S (1.28 g, 2.7 mmol) was dissolved in 30 ml ethanol. 2Nsodium hydroxide (1.28 g) and Pd/C (%10) (0.128 g, 10% of the weight ofstarting material) was added to the solution. The reaction washydrogenated at ambient pressure and temperature for 12 hours. Thereaction mixture was filtered by using a membrane filter (13, 0.22 μm),and the filtrate was concentrated in vacuo leaving a yellow oil. Thelatter was dissolved in DCM and extracted with water, dried over MgSO₄and the solvent removed leaving a colorless oil (0.46 g, 39% yield). Thematerial was used directly in the next step.

Preparation of1-(2-Methanesulphonamidephenoxy)-3(3,4-dichlorophenylethylamino)-2-propanol(17-S)

Compound 17d-S (0.460 g, 1.05 mmol) was dissolved in DCM and cooled to0° C. followed by addition of diisopropylamine (0.149 g, 0.2 ml, 1.15mmol) and methanesulfonylchloride (0.132 g, 0.1 ml, 1.15 mmol). Thereaction mixture was stirred at 0° C. for 2 hours, then warmed to roomtemperature slowly, and stirred at room temperature for another 16hours. Solvent was evaporated leaving a yellow brown oil. The latter wasadded to 50 ml of 1N HCl solution, stirred at room temperature for 4hours and extracted with DCM. The water layer was removed under reducedpressure, and the resulting solid was recrystallized from ethanol/etherto give the hydrochloride salt of compound 17-S.

¹H-NMR (DMSO-d₆) δ 2.34 (s, 3H), 2.93-3.39 (m, 6H), 3.94-4.10 (m, 2H),4.15-4.30(m, 1H), 6.55-7.03 (m, 2H), 7.24-7.60 (m, 5H), 8.74 (s, 1H).

The syntheses of compounds 18 and 19 are shown in scheme 6.

Preparation of1-(4-Methanesulphonamidophenoxy)-3-(N-acetyl-3,4-dichloro-phenylethylamino)-2-propylacetate (18-S)

Compound 5-S (0.303 g, 0.7 mmol) and a catalytic amount of4-(N,N-dimethylamino)pyridine were dissolved in acetic anhydride (1 ml)and pyridine (1 ml) and stirred at room temperature overnight. Thereaction was poured into 10 ml ice-water and extracted with DCM. Theorganic layer was dried over MgSO₄, and evaporated. The residue waspurified with flash chromatography using ethyl acetate:DCM (30:70)solvent to give as a colorless oil (75% yield).

¹H-NMR (CDCl3) δ 1.96 (s, 3H), 2.08 (s, 3H), 2.82 (dd, 2H), 3.39 (dd,2H), 3.44 (s, 3H), 3.56 (dd, 2H), 4.07, (dd, Hα, 1H), 4.11 (dd, Hβ, 1H),5.23-5.35 (m, 1H), 6.96 (d, 2H), 7.03 (dq, 1H), 7.20 (dq, 2H), 7.30 (dd,1H), 7.37 (dd, 1H).

Compound 18-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid.

Preparation ofN-(3,4-dichlorophenyl)ethyl-5-(4-methanesulphonamidophenoxy)methyl-oxazolidine-2-one(19-S)

Compound 5S (0.303 g, 0.7 mmol), 1,1′-carbonyldiimidazole (0.147 g,0.906 mmol) and a catalytic amount of 4-(N,N-dimethylamino)pyridine weredissolved in 10 ml benzene. After 12 hours refluxing the solvent wasevaporated, and the residue was purified with flash chromatography usingethyl acetate:DCM (30:70) solvent to give a colorless oil (85% yield).

¹H-NMR (CDCl₃) δ 2.88 (t, 2H), 2.95 (s, 3H), 3.42-3.62 (m, 4H), 4.02(dd, 2H), 4.76-4.82 (m, 1H), 6.51 (s, 1H), 6.83 (dd, 2H), 7.09 (dd, 1H),7.20 (dd, 2H), 7.32 (d, 1H), 7.35 (d, 1H). Compound 19-S was dissolvedin ethanol and treated with HCl gas to provide the HCl salt as a whitesolid.

The synthesis of compound 20 is shown in Scheme 7.

Preparation of (S)-Glycidyl N-methyl-N-Methanesulfonyl-p-AminophenylEther (20a-S)

A solution of compound 3-S (0.243 g, 1 mmol) and potassium carbonate(0.166 g, 1.2 mmol) in 20 ml acetone was stirred for 1 hour at roomtemperature, then methyl iodide (0.142 g, 0.062 ml, 1 mmol) was addeddropwise at room temperature. After stirring for 8 hours, the reactionwas filtered and the solvent evaporated to finish a white solid that wasused directly in the next step (0.2 g, 78% yield).

¹H-NMR (CDCl₃) δ 2.76 (dd, 1 H), 2.83 (s, 3H), 2.92 (t, 1H), 3.28 (s,3H), 3.33-3.39 (m 1H), 3.93 (dd, 1H), 4.24 (dd, 1H), 6.92 (dd, 2H), 7.29(dd, 2H).

Preparation of(S)-1-(4-N-methyl-methanesulphonamidephenoxy)-3-(3,4dichlorophenylethylamino)-2-propanol(20-S)

Compound 20a-S (0.2 g, 0.8 mmol) and 3,4-dichloropenylethylamine (0.147g, 0.11 ml, 0.8 mmol) were dissolved in 5 ml ethanol, refluxed for 5hours, and relieved of solvent by evaporation. The residue was purifiedby flash chromatography using dichloromethane:methanol (90:10) solventto give the product as a white solid (80% yield).

¹H-NMR (CDCl₃) δ 2.72-2.78 (m, 2H), 2.80 (s, 3H), 2.83-2.93 (m, 4H),3.24 (s, 3H), 3.93, (d, 2H), 4.00-4.04 (m, 1H), 6.85 (dd, 2H), 7.02 (dd,1H), 7.24 (dd, 2H), 7.26 (d, 1H), 7.31 (d, 1H).

Compound 20-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid.

Compound 21 was prepared in a manner similar to compound 5 (Scheme 8)

Preparation of (S)-Glycidyl N-benzenesulfonyl-p-Aminophenyl Ether(21a-S)

Compound 2-S (0.423 g, 2.56 mmol) in 20 ml anhydrous DCM at 0° C. wascombined with N,N-diisopropyl-N-ethylamine (0.364 g, 0.49 ml, 2.82mmol). After stirring for 15 minutes, benzenesulfonyl chloride (0.497 g,0.36 ml, 2.82 mmol) was added dropwise at 0° C., and the reaction wasstirred for 3 hours. The reaction solution was extracted with water andwashed with brine; the organic phase dried and evaporated. The residuewas purified with flash chromatography using ethyl acetate:DCM (30:70)solvent to give a white solid (75% yield).

¹H-NMR (CDCl₃) δ 2.74 (dd, 1H), 2.90 (t, 1H), 3.31-3.36 (m 1H), 3.86(dd, 1H), 4.18 (dd, 1H), 6.66 (s, 1H), 6.77 (dd, 2H), 6.97 (dd, 2H),7.42 (t, 2H), 7.52 (dd, 1H), 7.70 (dd, 2H).

Compound 21a-S (0.620 g, 2.0 mmol) and 3,4-dichloropenylethylamine(0.386, 0.30 ml, 2.0 mmol) were dissolved in 25 ml ethanol and refluxedfor 16 hours. The solvent was then evaporated and the residue waspurified by flash chromatography using dichloromethane:methanol (90:10)solvent to give the product (90% yield).

¹H-NMR (CDCl₃) δ 2.73-2.94 (m, 6H), 3.89, (dd, Hα, 1H), 3.91 (s, Hβ,1H), 3.97-4.01 (m, 1H), 6.74 (dd, 2H), 6.94 (dd, 2H), 7.03 (dd, 1H),7.29 (d, 1H), 7.34 (d, 1H), 7.43 (t, 2H), 7.52 (dd, 1H), 7.67 (dd, 2H).

Compound 21-S was dissolved in ethanol and treated with HCl gas toprovide the HCl salt as a white solid.

The synthesis of compound 22 was accomplished in a single step (Scheme9).

Preparation of(S)-1-(4-Nitrophenoxy)3-(3,4-dichlorophenylethylamino)-2propanol (22-S)

Compound 1-S (0.195 g, 1 mmol) and 3,4-dichloropenylethylamine (0.190 g,0.15 ml, 1 mmol) were dissolved in 5 ml ethanol and refluxed for 2hours. After 2 hours, a solid precipitated from the reaction (0.296 g,77% yield). It proved to be pure by NMR and TLC.

¹H-NMR (CDCl₃) δ 2.74-2.80 (m, 3H), 2.86-2.97 (m, 3H), 4.02-4.08 (m,3H), 6.96 (dd, 2H), 7.04 (dd, 1H), 7.3 1 (d, 1H), 7.36 (d, 1H), 8.20(dd, 2H).

1-20. (canceled)
 21. A compound selected from the group consisting of(R)- or (S)-enantiomers and racemic mixtures of a compound of theformula:

wherein one of R₉, R₁₀, R₁₁, R₁₂ and R₁₈ is

where R₁₃ is alkyl, aralkyl or aryl; R₁₇ is H or lower alkyl; and theothers of R₉, R₁₀, R₁₁, R₁₂ and R₁₈ are H, F, Cl, Br, I or lower alkyl;wherein either I) A is selected from the group consisting of:

wherein R₁, R₄, and R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₃ is independently O,S, NH or N(lower alkyl); R₂ is N, and R₁₆ is C-alkyl, C-aralkyl orC-aryl;

wherein R₁ and R₅ are independently selected from the group consistingof H, F, Cl, Br, I and O(lower alkyl); R₂ is independently O, S, NH orN(lower alkyl); R₃ is N; and R₁₆ is C-alkyl, C-aralkyl or C-aryl;

wherein R₁ is independently O, S, NH or N(lower alkyl); and R₂ throughR₄ are independently selected from the group consisting of H, F, Cl, Br,I and O(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O;

wherein R₁,is selected from the group consisting of O, S, NH or N(loweralkyl); and R₂ and R₃ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); or R₂ and R₃ takentogether are O—CH₂—O, and R₄ is N;

wherein R₂ selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); R₃ is selected from the group consisting of O, S, NH orN(lower alkyl); and R₄ is N;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is N, and R₃ and R₄ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl);

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ and R₄ are N, and R₃ is independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl);

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); and R₃ and R₄ are N;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); and R₂, R₃ and R₄ are N;

wherein R₁ and R₃ are independently selected from the group consistingof O, S, NH and N(lower alkyl); and R₂, R₂′ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); and

wherein R₁ and R₂ are independently selected from the group consistingof O, S, NH and N(lower alkyl); and R₂′, and R₃ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); and B is selected from the group consisting of:

wherein R₆ and R₆′ are independently H or F; and R₇ is H, lower n-alkyl,CH₂Ar, CH₂CH₂Ar, CH₂CHFAr, or CH₂CF₂Ar; and R₈ is OH, O(lower alkyl); Aris aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,6-difluorophenyl, 2,3,4-trifluorophenyl, or2,3,4,5,6-pentafluorophenyl;

wherein R₆ and R₆′ are independently H or F; R₇ is CH₂ and R₈ is O;

wherein R₅, R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is OH, or O(lower alkyl);

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)2; and R₈ is OH, or O(lower alkyl);

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is OH, or O(lower alkyl); and n=1-3; or II) A is

wherein R₁ and R₅ are independently H or F; R₂, R₃ and R₄ areindependently selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O; and B isselected from the group consisting of:

wherein R₆ and R₆′ are independently H or F; and R₇ is CH₂Ar, CH₂CH₂Ar,CH₂CHFAr, or CH₂CF₂Ar, where Ar is 2,3,4,5,6-pentafluorophenyl; and R₈is OH, O(lower alkyl);

wherein R₆ and R₆′ are independently H or F; R₇ is CH₂ and R₈ is O;

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is OH, or O(lower alkyl); and

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is OH, or O(lower alkyl); and n=1-3; or III) A isselected from the group consisting of:

wherein R₁ and R₅ are independently H or F; R₂, R₃ and R₄ areindependently selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O;

wherein R₁, R₄, and R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₃ is independently O,S, NH or NR, R₂ is N, and R₁₆ is C-alkyl, C-aralkyl or C-aryl;

wherein R₁, R₄, and R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₂ is independently O,S, NH or N(lower alkyl); R₃ is N; and R₁₆ is C-alkyl, C-aralkyl orC-aryl;

wherein R₁ is independently O, S, NH or N(lower alkyl); and R₂ throughR₄ are independently selected from the group consisting of H, F, Cl, Br,I and O(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O;

wherein R₁, is selected from the group consisting of O, S, NH or N(loweralkyl); and R₂ and R₃ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); or R₂ and R₃ takentogether are O—CH₂—O, and R₄ is N;

wherein R₂ selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); R₃ is selected from the group consisting of O, S, NH orN(lower alkyl); and R₄ is N;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is N, and R₃ and R₄ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl);

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ and R₄ are N, and R₃ is independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl);

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); and R₃ and R₄ are N;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); and R₂, R₃ and R₄ are N;

wherein R₁ and R₃ are independently selected from the group consistingof O, S, NH and N(lower alkyl); and R₂, R₂′ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); and

wherein R₁ and R₂ are independently selected from the group consistingof O, S, NH and N(lower alkyl); and R₂′, and R₃ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); and B is selected from the group consisting of:

wherein R₆ and R₆′ are independently H or F; and R₇ is H, lower n-alkyl,CH₂Ar, CH₂CH₂Ar, CH₂CHFAr, or CH₂CF₂Ar; Ar is aryl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl,2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; and R₈ is F;

wherein R₅, R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is F;

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is F; and

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; R₈ is F; and n=1-3; and pharmaceutically acceptable salts,enantiomers, enantiomeric mixtures, and mixtures of the foregoing. 22.The compound of claim 21 in combination with a suitable pharmaceuticalcarrier.
 23. The compound of claim 21 selected from (R)- and(S)-enantiomers and mixtures thereof of compounds selected from thegroup consisting of:

wherein R₁ and R₅ are independently H or F; and R₂, R₃ and R₄ areindependently selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O; R₆ and R₆′ areindependently H or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selectedfrom the group consisting of H, F, Cl, Br, I and lower alkyl; and R₁₃ isalkyl, aralkyl or aryl; and when R₁ and R₅ are H; R₇ is selected fromthe group consisting of CH₂Ar, CH₂CH₂Ar, CH₂CHFAr and CH₂CF₂Ar, where Aris 2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(lower alkyl) or F; and whenone of R₁ or R₅ is F and the other is H or F; R₇ is CH₂Ar, CH₂CH₂Ar,CH₂CHFAr, or CH₂CF₂Ar, where Ar is 2,3,4,5,6-pentafluorophenyl; R₈ is OHor F;

wherein R₁ and R₅ are independently H or F; R₂ is N; R₃ is O, S, NH orN(lower alkyl); R₄ is selected from the group consisting of H, F, Cl,Br, I and O(lower alkyl); R₆ and R₆′ are independently H or F; R₇ isselected from the group consisting of H, lower n-alkyl, CH₂Ar, CH₂CH₂Ar,CH₂CHFAr and CH₂CF₂Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(lower alkyl) or F; R₉, R₁₀, R₁₁and R₁₂ are independently selected from the group consisting of H, F,Cl, Br, I and lower alkyl; R₁₃ is alkyl, aralkyl or aryl; and R₁₆ isC-alkyl, C-aralkyl or C-aryl;

wherein R₁ and R₅ are independently H or F; R₂ is independently O, S, NHor N(lower alkyl); R₃ is N; R₄ is selected from the group consisting ofH, F, Cl, Br, I and O(lower alkyl); R₆ and R₆′ are independently H or F;R₇ is selected from the group consisting of H, lower n-alkyl, CH₂Ar,CH₂CH₂Ar, CH₂CHFAr and CH₂CF₂Ar, where Ar is aryl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl,2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(loweralkyl) or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from thegroup consisting of H, F, Cl, Br, I and lower alkyl; R₁₃ is alkyl,aralkyl or aryl; and R₁₆ is C-alkyl, C-aralkyl, or C-aryl;

wherein R₁ through R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and OR₁₄; or R₂ and R₃ taken together areO—CH₂—O; R₆ and R₆′ are independently H or F; R₇ is CH₂, R₈ is O; R₉,R₁₀, R₁₁ and R₁₂ are independently selected from the group consisting ofH, F, Cl, Br, I and lower alkyl; R₁₃ is alkyl, aralkyl or aryl; R₁₄ isC-alkyl, C-aralkyl or C-aryl;

wherein R₁, R₄ and R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₂ is O, S, NH orN(lower alkyl); R₃ is N; R₆ and R₆′ are independently H or F; R₇ is CH₂;R₈ is O; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the groupconsisting of H, F, Cl, Br, I and lower alkyl; R₁₃ is alkyl, aralkyl oraryl; and R₁₆ is C-alkyl, C-aralkyl or C-aryl;

wherein R₁, R₄ and R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₂ is N; R₃ is O, S,NH or N(lower alkyl); R₆ and R₆′ are independently H or F; R₇ is CH₂; R₈is O; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the groupconsisting of H, F, Cl, Br, I and lower alkyl, R₁₃ is alkyl, aralkyl oraryl; and R₁₆ is C-alkyl, C-aralkyl or C-aryl;

wherein R₁ and R₄ are independently selected from the group consistingof H, F, Cl, Br, I and OR₁₄; R₂ and R₃ are independently selected fromthe group consisting of F, Cl, Br, I, and OR₁₄, or R₂ and R₃ takentogether are O—CH₂—O; R₅, R₆ and R₇ are independently CH₂, CH(loweralkyl) or C(lower alkyl)₂; R₁ is F; R₉, R₁₀, R₁₁ and R₁₂ areindependently selected from the group consisting of H, F, Cl, Br, I orlower alkyl; R₁₃ is alkyl, aralkyl or aryl; and R₁₄ is C-alkyl,C-aralkyl or C-aryl;

wherein R₁ and R₄ are independently selected from the group consistingof H, F, Cl, Br, I and OR₁₄; R₂ is selected from the group consisting ofO, S, NH or N(lower alkyl); R₃ is N; R₅, R₆ and R₇ are independentlyCH₂, CH(lower alkyl) or C(lower alkyl)₂; R₈ is OH, O(lower alkyl), or F;R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the groupconsisting of H, F, Cl, Br, I and lower alkyl, R₁₃ is alkyl, aralkyl oraryl; R₁₄ is C-alkyl, C-aralkyl or C-aryl; and R₁₆ is C-alkyl,C-aralkyl, or C-aryl;

wherein R₁ and R₄ are independently selected from the group consistingof H, F, Cl, Br, I and OR₁₄; R₂ is N; R₃ is selected from the groupconsisting of O, S, NH and N(lower alkyl); R₅, R₆ and R₇ areindependently CH₂, CH(lower alkyl) or C(lower alkyl)₂; R₈ is OH, O(loweralkyl), or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from thegroup consisting of H, F, Cl, Br, I and lower alkyl, R₁₃ is alkyl,aralkyl or aryl; R₁₄ is C-alkyl, C-aralkyl or C-aryl; and R₁₆ isC-alkyl, C-aralkyl, or C-aryl;

wherein R₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and OR₁₄, or R₂ and R₃ taken together areO—CH₂—O; R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀, R₁₁ and R₁₂ areindependently selected from the group consisting of H, F, Cl, Br, I andlower alkyl, R₁₃ is alkyl, aralkyl or aryl; R₁₄ is C-alkyl, C-aralkyl orC-aryl; and n=1-3;

wherein R₁, R₄ and R₅ are independently selected form the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₂ is O, S, NH orN(lower alkyl); R₃ is N; R₆ and R₇ are independently CH₂, CH(loweralkyl) or C(lower alkyl)₂; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀, R₁₁and R₁₂ are independently selected from the group consisting of H, F,Cl, Br, I and lower alkyl, R₁₃ is alkyl, aralkyl or aryl; R₁₆ isC-alkyl, C-aralkyl or C-aryl; and n=1-3;

wherein R₁, R₄ and R₅ are independently selected form the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₂ is N; R₃ is O, S,NH or N(lower alkyl); R₆ and R₇ are independently CH₂, CH(lower alkyl)or C(lower alkyl)₂; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀, R₁₁ and R₁₂are independently selected from the group consisting of H, F, Cl, Br, Iand lower alkyl; R₁₃ is alkyl, aralkyl or aryl; R₁₆ is C-alkyl,C-aralkyl or C-aryl; and n=1-3;

wherein R₁, R₂, R₃, R₄ and R₅ are independently selected from the groupg of H, F, Cl, Br, I and O(lower alkyl); or R₂ and R₃ taken together areO—CH₂—O; R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀, R₁₁ and R₁₂ areindependently selected from the group consisting of H, F, Cl, Br, I orlower alkyl; R₁₃ is alkyl, aralkyl or aryl; and n=1-3;

wherein R₁, R₄ and R₅ are independently selected form the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₂ is O, S, NH orN(lower alkyl); R₃ is N; R₆ and R₇ are independently CH₂, CH(loweralkyl) or C(lower alkyl)₂; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀, R₁₁and R₁₂ are independently selected from the group consisting of H, F,Cl, Br, I and lower alkyl, R₁₃ is alkyl, aralkyl or aryl; R₁₆ isC-alkyl, C-aralkyl or C-aryl; R₁₆ is C-alkyl, C-aralkyl or C-aryl; andn=1-3;

wherein R₁, R₄ and R₅ are independently selected form the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₂ is N; R₃ is O, S,NH or N(lower alkyl); R₆ and R₇ are independently CH₂, CH(lower alkyl)or C(lower alkyl)₂; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀, R₁₁ and R₁₂are independently selected from the group consisting of H, F, Cl, Br, Iand lower alkyl, R₁₃ is alkyl, aralkyl or aryl; R₁₆ is C-alkyl,C-aralkyl or C-aryl, and n=1-3;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂, R₃ and R₄ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₅ is H; R₆ and R₆′are independently H or F; R₇ is H, lower alkyl, CH₂Ar, CH₂CH₂Ar,CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀,R₁₁ and R₁₂ are independently selected from the group consisting of H,F, Cl, Br, I and lower alkyl; R₁₃ is alkyl, aralkyl or aryl;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ and R₃ are independently selected from the group consistingof H, F, Cl, Br, I and O(lower alkyl); or R₂ and R₃ taken together areO—CH₂—O; R_(4,) R₅ and R₆ are independently CH₂, CH(lower alkyl) orC(lower alkyl)₂; R₇ is H, R₈ is OH, O(lower alkyl), or F; R₉, R₁₀, R₁₁and R₁₂ are independently selected from the group consisting of H, F,Cl, Br, I and lower alkyl; R₁₃ is alkyl, aralkyl or aryl;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ and R₃ are independently selected from the group consistingof H, F, Cl, Br, I and O(lower alkyl); or R₂ and R₃ taken together areO—CH₂—O; R₄ is N; R₅ is H; R₆ and R₆′ are independently H or F; R₇ is H,lower alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl,2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(loweralkyl), or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from thegroup consisting of H, F, Cl, Br, I and lower alkyl; R₁₃ is alkyl,aralkyl or aryl;

wherein R₁ and R₂ are independently selected from the group consistingof H, F, Cl, Br, I and O(lower alkyl); R₃ is selected from the groupconsisting of O, S, NH and N(lower alkyl); R₄ is N; R₅ is H; R₆ and R₆′are independently H or F; R₇ is H, lower alkyl, CH₂Ar, CH₂CH₂Ar,CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀,R₁₁ and R₁₂ are independently selected from the group consisting of H,F, Cl, Br, I and lower alkyl; R₁₃ is alkyl, aralkyl or aryl;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is N; R₃ and R₄ are is selected from the group consisting ofH, F, Cl, Br, I and O(lower alkyl); R₅ is H, R₆ and R₆′ areindependently H or F; R₇ is H, lower alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr orCH₂CF₂Ar, where Ar is aryl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀,R₁₁ and R₁₂ are independently selected from the group consisting of H,F, Cl, Br, I and lower alkyl; R₁₃ is alkyl, aralkyl or aryl;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is N; R₃ is selected from the group consisting of H, F, Cl,Br, I and O(lower alkyl); R₄, R₅ and R₆ are independently CH₂, CH(loweralkyl) or C(lower alkyl); R₇ is H; R₈ is OH, O(lower alkyl), or F; R₉,R₁₀, R₁₁ and R₁₂ are independently selected from the group consisting ofH, F, Cl, Br, I or lower alkyl; R₁₃ is alkyl, aralkyl or aryl;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₃ is selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); R₂ and R₄ are N; R₅ is H; R₆ and R₆′ are independently Hor F; R₇ is H, lower alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, whereAr is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,6-difluorophenyl, 2,3,4-trifluorophenyl, or2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀,R₁₁ and R₁₂ are independently selected from the group consisting of H,F, Cl, Br, I and lower alkyl; R₁₃ is alkyl, aralkyl or aryl;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); R₃ and R₄ are N; R₅ is H; R₆ and R₆′ are independently Hor F; R₇ is H, lower alkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, whereAr is aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,6-difluorophenyl, 2,3,4-trifluorophenyl, or2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(lower alkyl), or F; R₉, R₁₀,R₁₁ and R₁₂ are independently selected from the group consisting of H,F, Cl, Br, I and lower alkyl; R₁₃ is alkyl, aralkyl or aryl;

wherein R₁ is selected from a group consisting of O, S, NH or N(loweralkyl); R₂, R₃ and R₄ are N; R₅ is H, R₆ and R₆′ are independently H orF; R₇ is selected from the group consisting of H, lower alkyl, CH₂Ar,CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl,2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(loweralkyl), or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from thegroup consisting of H, F, Cl, Br, I and lower alkyl; R₁₃ is alkyl,aralkyl or aryl;

wherein R₁ and R₃ are independently selected from the group consistingof O, S, NH and N(lower alkyl); R₂, R₂′ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); R₅ is H; R₆ and R₆′ are independently H or F; R₇ is H, loweralkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl,2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(loweralkyl), or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from thegroup consisting of H, F, Cl, Br, I or lower alkyl; R₁₃ is alkyl,aralkyl or aryl;

wherein R₁ and R₂ are independently selected from the group consistingof O, S, NH and N(lower alkyl); R₂′, R₃ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); R₅ is H; R₆ and R₆′ are independently H or F; R₇ is H, loweralkyl, CH₂Ar, CH₂CH₂Ar, CH₂CHFAr or CH₂CF₂Ar, where Ar is aryl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl,2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; R₈ is OH, O(loweralkyl), or F; R₉, R₁₀, R₁₁ and R₁₂ are independently selected from thegroup consisting of H, F, Cl, Br, I and lower alkyl; R₁₃ is alkyl,aralkyl or aryl;

wherein R₁ and R₄ are independently selected from the group consistingof O, S, NH and N(lower alkyl); R₂ and R₃ are independently selectedfrom the group consisting of H, F, Cl, Br, I and O(lower alkyl); or R₂and R₃ taken together are O—CH₂—O; R₅, R₆ and R₇ are independently CH₂,CH(lower alkyl) or C(lower alkyl); R₈ is OH, or O(lower alkyl), or F;R₉, R₁₀, R₁₁ and R₁₂ are independently selected from the groupconsisting of H, F, Cl, Br, I and lower alkyl; R₁₃ is alkyl, aralkyl oraryl; and

wherein R₁ and R₂ are independently selected from the group consistingof O, S, NH and N(lower alkyl); R₃ and R₄ are independently selectedfrom the group consisting of H, F, Cl, Br, I and O(lower alkyl) or R₃and R₄ taken together are O—CH₂—O; R₅, R₆ and R₇ are independently CH₂,CH(lower alkyl) or C(lower alkyl); R₈ is OH or F; R₉, R₁₀, R₁₁ and R₁₂are independently selected from the group consisting of H, F, Cl, Br, Iand lower alkyl; R₁₃ is alkyl, aralkyl or aryl.
 24. The compound ofclaim 21 selected from the group consisting of the (S) or (R) forms of:1-(4-Methanesulphonamidophenoxy)-3-(N-(2,3,4,5,6-pentafluoro-benzyl)-3,4-di-chlorophenylethylamino)-2-propanol;mixtures thereof and pharmaceutically acceptable salts thereof.
 25. Thecompound of claim 21 wherein A is selected from the group consisting of:

wherein R₁, R_(4,) and R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₃ is independently O,S, NH or N(lower alkyl); R₂ is N, and R₁₆ is C-alkyl, C-aralkyl orC-aryl;

wherein R₁ is independently O, S, NH or N(lower alkyl); and R₂ throughR₄ are independently selected from the group consisting of H, F, Cl, Br,I and O(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O;

wherein R₁, is selected from the group consisting of O, S, NH or N(loweralkyl); and R₂ and R₃ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); or R₂ and R₃ takentogether are O—CH₂—O, and R₄ is N;

wherein R₂ selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); R₃ is selected from the group consisting of O, S, NH orN(lower alkyl); and R₄ is N;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is N, and R₃ and R₄ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl);

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ and R₄ are N, and R₃ is independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl);

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); and R₃ and R₄ are N;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); and R₂, R₃ and R₄ are N;

wherein R₁ and R₃ are independently selected from the group consistingof O, S, NH and N(lower alkyl); and R₂, R₂′ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); and

wherein R₁ and R₂ are independently selected from the group consistingof O, S, NH and N(lower alkyl); and R₂′, and R₃ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); and wherein B is

wherein R₆ and R₆′ are independently H or F; and R₇ is H, lower n-alkyl,CH₂Ar, CH₂CH₂Ar, CH₂CHFAr, or CH₂CF₂Ar; Ar is aryl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl,2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; and R₈ is OH,O(lower alkyl), or F.
 26. The compound of claim 27 wherein R₇ islower-alkyl.
 27. The compound of claim 27 wherein R₇ is CH₂Ar.
 28. Thecompound of claim 27 wherein R₈ is OH.
 29. The compound of claim 27wherein R₈ is F.
 30. The compound of claim 21 wherein A is

wherein R₁ and R₅ are independently H or F; R₂, R₃ and R₄ areindependently selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O; and B is

wherein R₆ and R₆′ are independently H or F; and R₇ is CH₂Ar, CH₂CH₂Ar,CH₂CHFAr, or CH₂CF₂Ar, where Ar is 2,3,4,5,6-pentafluorophenyl; and R₈is OH, O(lower alkyl).
 31. The compound of claim 30 wherein R₇ is CH₂Ar,where Ar is 2,3,4,5,6-pentafluorophenyl.
 32. The compound of claim 30wherein R₈ is OH.
 33. The compound of claim 30 wherein R₈ is O(loweralkyl).
 34. The compound of claim 25 wherein A is

wherein R₁ and R₅ are independently H or F; R₂, R₃ and R₄ areindependently selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O; and B is

wherein R₆ and R₆′ are independently H or F; R₇ is CH₂ and R₈ is O. 35.The compound of claim 21 wherein A is

wherein R₁ and R₅ are independently H or F; R₂, R₃ and R₄ areindependently selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O; and B is

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is OH, O(lower alkyl).
 36. A compound of claim 21wherein A is selected from the group consisting of:

wherein R₁ and R₅ are independently H or F; R₂, R₃ and R₄ areindependently selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O; and B isselected from the group consisting of:

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; R₈ is OH, O(lower alkyl); and n=1-3.
 37. The compound of claim21 wherein A is

wherein R₁ and R₅ are independently H or F; R₂, R₃ and R₄ areindependently selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O; and wherein Bis

wherein R₆ and R₆′ are independently H or F; and R₇ is H, lower n-alkyl,CH₂Ar, CH₂CH₂Ar, CH₂CHFAr, or CH₂CF₂Ar; Ar is aryl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl,2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; and R is F. 38.The compound of claim 37 wherein R₇ is lower alkyl.
 39. The compound ofclaim 37 wherein R₇ is CH₂Ar.
 40. The compound of claim 37 wherein R₃and R₄ are Cl.
 41. The compound of claim 37 wherein R₃ and R₄ areO(lower alkyl).
 42. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 21 optionally ina pharmaceutically acceptable carrier.
 43. The pharmaceuticalcomposition of claim 42 suitable for oral administration.
 44. Thepharmaceutical composition of claim 42 suitable for parenteraladministration.
 45. A method of treating neurodegeneration associatedwith a pathological condition characterized by lowered brain-tissue pH,said method comprising administering to a patient in need of suchtreatment a pharmaceutically effective amount of a compound havingenhanced NMDA receptor blocking activity at said lowered brain-tissue pHover normal brain-tissue pH, said compound being selected from the groupconsisting of (R)- or (S)-enantiomers and racemic mixtures of a compoundof the formula:

wherein one of R₉, R₁₀, R₁₁, R₁₂ and R₁₈ is

where R₁₃ is alkyl, aralkyl or aryl; R₁₇ is H or lower alkyl; and theothers of R₉, R₁₀, R₁₁, R₁₂ and R₁₈ are H, F, Cl, Br, I or lower alkyl;wherein either I) A is selected from the group consisting of:

wherein R₁, R_(4,) and R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₃ is independently O,S, NH or N(lower alkyl); R₂ is N, and R₁₆ is C-alkyl, C-aralkyl orC-aryl;

wherein R₁ and R₅ are independently selected from the group consistingof H, F, Cl, Br, I and O(lower alkyl); R₂ is independently O, S, NH orN(lower alkyl); R₃ is N; and R₁₆ is C-alkyl, C-aralkyl or C-aryl;

wherein R₁ is independently O, S, NH or N(lower alkyl); and R₂ throughR₄ are independently selected from the group consisting of H, F, Cl, Br,I and O(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O;

wherein R₁, is selected from the group consisting of O, S, NH or N(loweralkyl); and R₂ and R₃ are independently selected from the groupconsisting of H, F, Cl, Br, I and O (lower alkyl); or R₂ and R₃ takentogether are O—CH₂—O, and R₄ is N;

wherein R₂ selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); R₃ is selected from the group consisting of O, S, NH orN(lower alkyl); and R₄ is N;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is N, and R₃ and R₄ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl);

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ and R₄ are N, and R₃ is independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl);

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); and R₃ and R₄ are N;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); and R₂, R₃ and R₄ are N;

wherein R₁ and R₃ are independently selected from the group consistingof O, S, NH and N(lower alkyl); and R₂, R₂′ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); and

wherein R₁ and R₂ are independently selected from the group consistingof O, S, NH and N(lower alkyl); and R₂′, and R₃ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); and B is selected from the group consisting of:

wherein R₆ and R₆′ are independently H or F; and R₇ is H, lower n-alkyl,CH₂Ar, CH₂CH₂Ar, CH₂CHFAr, or CH₂CF₂Ar; and R₈ is OH, O(lower alkyl); Aris aryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,6-difluorophenyl, 2,3,4-trifluorophenyl, or2,3,4,5,6-pentafluorophenyl;

wherein R₆ and R₆′ are independently H or F; R₇ is CH₂ and R₈ is O;

wherein R₅, R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is OH, or O(lower alkyl);

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is OH, or O(lower alkyl);

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is OH, or O(lower alkyl); and n=1-3; or II) A is

wherein R₁ and R₅ are independently H or F; R₂, R₃ and R₄ areindependently selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O; and B isselected from the group consisting of:

wherein R₆ and R₆′ are independently H or F; and R₇ is CH₂Ar, CH₂CH₂Ar,CH₂CHFAr, or CH₂CF₂Ar, where Ar is 2,3,4,5,6-pentafluorophenyl; and R₈is OH, O(lower alkyl);

wherein R₆ and R₆′ are independently H or F; R₇ is CH₂ and R₈ is O;

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is OH, or O(lower alkyl); and

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is OH, or O(lower alkyl); and n=1-3; or III) A isselected from the group consisting of:

wherein R₁ and R₅ are independently H or F; R₂, R₃ and R₄ areindependently selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O;

wherein R₁, R₄, and R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₃ is independently O,S, NH or NR, R₂ is N, and R₁₆ is C-alkyl, C-aralkyl or C-aryl;

wherein R₁, R₄, and R₅ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); R₂ is independently O,S, NH or N(lower alkyl); R₃ is N; and R₁₆ is C-alkyl, C-aralkyl orC-aryl;

wherein R₁ is independently O, S, NH or N(lower alkyl); and R₂ throughR₄ are independently selected from the group consisting of H, F, Cl, Br,I and O(lower alkyl); or R₂ and R₃ taken together are O—CH₂—O;

wherein R₁, is selected from the group consisting of O, S, NH or N(loweralkyl); and R₂ and R₃ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl); or R₂ and R₃ takentogether are O—CH₂—O, and R₄ is N;

wherein R₂ selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); R₃ is selected from the group consisting of O, S, NH orN(lower alkyl); and R₄ is N;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is N, and R₃ and R₄ are independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl);

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ and R₄ are N, and R₃ is independently selected from the groupconsisting of H, F, Cl, Br, I and O(lower alkyl);

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); R₂ is selected from the group consisting of H, F, Cl, Br, I andO(lower alkyl); and R₃ and R₄ are N;

wherein R₁ is selected from the group consisting of O, S, NH and N(loweralkyl); and R₂, R₃ and R₄ are N;

wherein R₁ and R₃ are independently selected from the group consistingof O, S, NH and N(lower alkyl); and R₂, R₂′ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); and

wherein R₁ and R₂ are independently selected from the group consistingof O, S, NH and N(lower alkyl); and R₂′, and R₃ and R₄ are independentlyselected from the group consisting of H, F, Cl, Br, I and O(loweralkyl); and B is selected from the group consisting of:

wherein R₆ and R₆′ are independently H or F; and R₇ is H, lower n-alkyl,CH₂Ar, CH₂CH₂Ar, CH₂CHFAr, or CH₂CF₂Ar; Ar is aryl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl,2,3,4-trifluorophenyl, or 2,3,4,5,6-pentafluorophenyl; and R₈ is F;

wherein R₅, R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is F;

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; and R₈ is F; and

wherein R₆ and R₇ are independently CH₂, CH(lower alkyl) or C(loweralkyl)₂; R₈ is F; and n=1-3; and pharmaceutically acceptable salts,enantiomers, enantiomeric mixtures, and mixtures of the foregoing.